Granulomatous Inflammation Pathology

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Contents

0.1 What is granulomatous inflammation pathology?

1 What is the significance of granulomatous inflammation?
2 What cytokines make granulomas?

What is granulomatous inflammation pathology?

Abstract – Granulomatous inflammation is a histologic pattern of tissue reaction which appears following cell injury. Granulomatous inflammation is caused by a variety of conditions including infection, autoimmune, toxic, allergic, drug, and neoplastic conditions.

The tissue reaction pattern narrows the pathologic and clinical differential diagnosis and subsequent clinical management. Common reaction patterns include necrotizing granulomas, non necrotizing granulomas, suppurative granulomas, diffuse granulomatous inflammation, and foreign body giant cell reaction.

Prototypical examples of necrotizing granulomas are seen with mycobacterial infections and non-necrotizing granulomas with sarcoidosis. However, broad differential diagnoses exist within each category. Using a pattern based algorithmic approach, identification of the etiology becomes apparent when taken with clinical context.

The pulmonary system is one of the most commonly affected sites to encounter granulomatous inflammation. Infectious causes of granuloma are most prevalent with mycobacteria and dimorphic fungi leading the differential diagnoses. Unlike the lung, skin can be affected by several routes, including direct inoculation, endogenous sources, and hematogenous spread.

This broad basis of involvement introduces a variety of infectious agents, which can present as necrotizing or non-necrotizing granulomatous inflammation. Non-infectious etiologies require a thorough clinicopathologic review to narrow the scope of the pathogenesis which include: foreign body reaction, autoimmune, neoplastic, and drug related etiologies.

What is granulomatous inflammation morphology?

Granulomatous inflammation is a distinctive pattern of chronic inflammation encountered in a limited number of infectious and non infectious conditions. It is a cellular attempt to contain an offending agent which is difficult to eradicate.

What makes up granulomatous inflammation?

Selected References – These references are in PubMed. This may not be the complete list of references from this article.

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What is the mechanism of granulomatous inflammation formation?

Abstract – The mononuclear phagocyte system is the central body defense called upon to deal with persistent foreign objects or irritants. Depending on circumstances, the macrophages function as phagocytes or secretory cells or both. Granulomas may form in the absence of immunologic modulation (foreign body granuloma) or they may develop under immunologic control (hypersensitivity granulomas).

In either case, the secretory products of macrophages are qualitatively similar and differ mainly in the total amounts produced.
If cell-mediated immunity dictates hypersensitivity granulomas as commonly taught, one has to explain what aberrent signals are sent from T cells or what abnormal message is perceived in the macrophages which causes them to differentiate to purely secretory epithelioid cells or produce such abnormal pathologic patterns as necrobiosis.

Alternatively, some granulomatous hypersensitivity reactions such as organized epithelioid cell granulomas may be initiated primarily by a macrophage secretion product with cellular immunity acting to amplify or promote granuloma formation and organization.

What is the difference between granulomatous and non granulomatous inflammation?

eye inflammation –

In uveitis: Granulomatous and nongranulomatous uveitis Uveitis is also classified as granulomatous (persistent eye inflammation with a grainy surface) and nongranulomatous. Granulomatous uveitis is characterized by blurred vision, mild pain, eye tearing, and mild sensitivity to light. Nongranulomatous uveitis is characterized by acute onset, pain, and intense

What is the significance of granulomatous inflammation?

POINT OF VIEW Viewpoint. Granulomatous inflammation T. de Brito; M.F. Franco GENERAL COMENTS Granulomatous inflammation may be defined as a type of chronic inflammation in which a compact collection of cells of the mononuclear phagocyte system 37, chiefly activated macrophages and cells derived from them are predominant 1, 39,

These cells are aggregated into well demarcated focal lesions and the designation granuloma (granule + oma = tumor) derives from this peculiar aspect. In addition, granulomas usually contain an admixture of other cells, especially lymphocytes and plasma cells, and, depending on their stage, fibroblasts 39,

Eosinophils are usually present in parasitic and fungal granulomas. The term activated macrophage implies either that an increase in the functional activity of the macrophage has occurred or that a new functional activity has appeared. Newly arrived monocytes are initially simple cells which progressively increase their nuclear euchromatin content, develop prominent nucleoli, extensive cytoplasm, free ribosomes, abundant Golgi apparatus, large lysosomes and finally acquire the morphology of the so-called activated macrophages.

The mononuclear phagocytic system as defined by VAN FURTH et al.37 has evolved from the reticulo-endothelial system concept elaborated by ASCHOFF and coworkers 4 and comprises the group of highly phagocytic mononuclear cells and their precursors which are widely distributed in the body; they share many morphologic and functional features and originate from the bone marrow.

Macrophages, monocytes, promonocytes, monoblasts, Kupffer cells, microglia and osteoclasts are all components of the system 27, Macrophages originate from bone marrow precursors via circulating monocytes through a maturation process which is accompanied by morphological and functional changes; the process continues even when macrophages enter the tissues, were they are also called histiocytes 1,

The turnover time in most instances is about one to two weeks 27,
The production of monocytes is under feedback control; peripheral macrophages and lymphocytes secrete factors that have both stimulatory and inhibitory actions on stem cell proliferation in the bone marrow.
Although exudation seems to be by far the most important source of macrophages in the inflammatory reaction, local histiocytic proliferation does occur 1, 39,

All granulomatogenic factors share one basic property, namely, they are poorly degradable materials. Thus, granulomatous inflammation can be regarded as a response to pathogens and persistent irritants of either exogenous or endogenous origin 21, Soluble materials, however, can also produce granulomas when they combine with endogenous macromolecules to form insoluble, undegradable compounds 29,

TYPES OF GRANULOMA Granulomas fall into two groups, namely foreign body or low turnover cell and epithelioid, hyper-sensitivity 12 or high turnover cell types 38, An inducing agent is often recognizable in foreign body granulomas, usually phagocytosed by macrophages and foreign body giant cells. The foreign body granuloma is a poorly organized granuloma with focal aggregates of macrophages intermixed with few lymphocytes and plasma cells.

Epithelioid cells are either scarce or absent. Cell kinetics shows that there is a low turnover of macrophages; the few dying cells are replaced either by new recruits from the circulation or by local cell proliferation. Macrophages of these low turnover lesions survive 4-8 weeks 1,

Granulomatogenic agents, although poorly degradable, are relatively inert and nontoxic to the cells.
Immune mechanisms are of minor importance in the pathogenesis of foreign body granulomas which may be regarded as “phagocytic granulomas”.
Macrophages and foreign body giant cell are frequently seen apposed to the inducing agent which is often observed internalized by the giant cell.

Two giant cell categories can be distinguished by their morphological characteristics which may be seen both in foreign body and epithelioid granulomas but in different proportions: the foreign body giant cell which shows nuclei randomly dispersed throughout the cytoplasm in a disorganized manner, and predominates in the foreign body granuloma, and the Langhans cell type which shows nuclei located at the cell margins and is seen in the epithelioid granuloma 1,

Both cells originate from fusion of macrophages rather than nuclear division and probably result from the attempt of two or more macrophages to phagocytose a single particle, which results in the fusion of their plasma membranes.
Foreign body giant cells mature into Langhans cells, probably by movements of the intracellular cytoskeleton 1,

Actin filaments are demonstrated both in macrophages and giant cells in the cell periphery and in microtubules radiating from the perinuclear into the peripheral cytoplasm. Actin filaments are important elements for the phagocytic function of these cells.

The distribution of the cytoskeletal components of these cells may be characteristic of free wandering cells since it is seen in other free cells such as polymorphonuclear leukocytes and fibroblasts 6,
At least one cytokine, the monocyte chemo-attractant protein 1 (MCP-1), which is released by monocytes following phagocytosis 18, may be involved in the foreign body granuloma formation.

Human monocytes have high affinity receptors for MCP and the release of this cytokine by macrophages which have ingested material of a biochemical or biological nature causes further monocyte recruitment and cell activation. Epithelioid or hypersensitivity granulomas are high turnover granulomas produced by irritants which are injurious to macrophages such as silica and infectious agents.

In these granulomas a high rate of recruitment and local division of macrophages are observed to compensate for the relatively short life span (usually only a few days) and high death rate of these cells within the lesion 1,
The causative agent, when present, is detected only in a small proportion of phagocytic cells, usually at the center of the granuloma.

Epithelioid granulomas consist of a cohesive collection of cells which range from phagocytic and activated macrophages to epithelioid cells. Epithelioid cells arrange themselves in layers or form discrete aggregates in the central part of the lesion or around necrotic areas.

They originate from macrophage precursors and have an elongated euchromatin nucleus, conspicuous nucleoli and an abudant cytoplasm with prominent endoplasmic reticulum and few lysosomes. The cells appear to be closely associated, and are interlocked by pseudopods in zipper-like arrays but with no junctional specialization.

Epithelioid cells show large numbers of pale-staining secretory vacuoles in the cytoplasm and little evidence of phagocytic activity 29, The vacuoles do not contain acid phosphatase, suggesting that they are not of lysosomal origin. Moreover, there is evidence that the expression of surface immune receptors (Fc and C3b) seen in macrophages is considerably reduced or absent in epithelioid cells.

At an early stage, epithelioid granulomas show an admixture of macrophages, few epithelioid cells and lymphocytes.
Lymphocytes at the center of the granuloma are mostly CD4 (helper-inducer) T lymphocytes 29,
When the granuloma matures, a halo of B and chiefly CD8 (suppressor-cytotoxic) T lymphocytes is observed at the periphery together with fibroblasts.

It is assumed that these T and B lymphocytes represent progressive clonal expansion specific for the antigen/s present in the granuloma. Giant cells, mostly of the Langhans type, are detected chiefly at the center of the lesion. They may express Fc and C3b surface receptors found in macrophages and they are able to phagocytose bacteria and fungi.

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IMMUNOPATHOGENESIS OF THE SCHISTOSOMAL GRANULOMA Among the experimental and human epithelioid granulomas, the immunopathogenesis of the schistosomal granuloma is one of the best studied. Schistosomiasis mansoni represents the first form of granulomatous inflammation that has been clearly shown to be of immunological origin 7, 8, 38,

Its formation is primarily a manifestation of cell mediated immunity (CMI) as demonstrated by passive transfer, association with other forms of CMI and response to immunosuppressive measures 7, 8, 38, Schistosomal eggs possess a fenestrated shell and it has been suggested that antigenic materials secreted by the embryo within might cross the shell through the pores.

The probable events leading to the schistosomal egg granuloma begin with antigen-presenting cells (APC), mostly macrophages, expressing major histocompatibility (MHC) class II antigens, interacting with T lymphocytes with production of cytokines.
At this stage gamma-interferon (gamma-IFN) appears to up-regulate the MHC class II display on APC and the induction of cytokines such as interleukin 1 (I11) and tumor necrosis factor (TNF) production by macrophages 20,

Ill in synergism with TNF plays an important role in granuloma induction in vitro 30, 36, Other cytokines such as MCP-1 amplify the inflammatory response and the recruitment of stimulated macrophages. Experimental data have recently shown that T cell cytokines such as I1-2 and I1-4 appear to play a proinflammatory role in granuloma formation while gamma-IFN down-modulates its formation during the peak phase 20,

In the schistosomal granuloma, eosinophils may be part of the CMI reaction and their depletion delays egg destruction.
Stimulated macrophages evolve to epithelioid and giant cells.
Lymphocytes and plasma cells form a halo surrounding the granuloma.
Different degrees of collagen synthesis due to an interaction of macrophages and lymphocytes with fibroblasts may also be seen at the periphery of the granuloma 7, 8,

Both human and experimental evidence 9, 10 has suggested that during the early phase of the granulomatous inflammation, the response consists of activated macrophages, few epithelioid and giant cells intermixed with CD4 (helper-inducer) T lymphocytes which cannot completely wall off the antigen/s present at the center of the granuloma.

As the granuloma matures, antigen/s become restricted to the miracidium and immunoglobulins, chiefly of the IgG class, are detected at the periphery, corresponding to the inflammatory halo, where immunoglobulin-producing cells are observed.
Epithelioid cells act as a barrier between antigens at the center and antibodies produced by B lymphocytes in the peripheral inflammatory halo; therefore these cells play a critical role in the granulomatous inflammation.

Slow permeation of antigens and antibodies, which probably takes place throughout the granuloma, allows antigen neutralization in small doses, thus preventing the local formation of large immuno-complexes which would produce marked tissue injury through complement activation.

The small antigen-antibody complexes formed may be removed by local macrophages 9, 10 ( Fig.1 ).
Though the deleterious role of the granulomatous inflammation, through the secretion of tissue-destructive substances by its cell population, has been extensively studied 8, it now appears that granuloma formation is intrinsically favorable to the host.

Viewed as a whole, the schistosomal egg granuloma may be regarded as an efficient structure which walls off antigen/s and harmful substances locally produced through a mixed, chiefly cellular but also local antibody-mediated immune response 9, 10, IMMUNOPATHOGENESIS OF THE P.

BRASILIENSIS GRANULOMA The P. brasiliensis granuloma is generally centered around one or more fungal cells and is composed of giant cells and epithelioid cells; therefore it is an epithelioid granuloma. Polymorphonuclear leukocytes may be observed close to the fungi in the central area; encircling the granuloma, there is a halo of mononuclear cells.

The granulomas may show central necrosis of the coagulative type in addition to central suppuration 15, Several findings in human and experimental paracoccidioidomycosis have indicated that the paracoccidioidal granuloma may represent an immune-specific response of the host to the fungus.

Paracoccidioidomycosis presents two polar clinical forms, namely the hyperergic pole which is characterized by localized infection, persistent cellular immune response and a compact epithelioid granuloma, and the anergic pole which is represented by disseminated infection, decreased cellular immunity and loose, parasite-rich, granulomatous inflammation.

The hyperergic type of reaction is typically seen in the patients with “ides” manifestations or with the sarcoidic form of the disease. The anergic pole in which granulomas have no ability to kill the fungal cells is reproduced in athymic mice as well as in patients with AIDS 15, 16, 17, 24,

The microanatomy of P.
Brasiliensis granulomas has been investigated by the use of immunohistochemical techniques and monoclonal antibodies to T-lymphocyte subsets.P.
Brasiliensis granulomas, both in patients and in experimentally infected mice, show a T-cell peripheral mantle around central aggregates of macrophages.

The majority of the lymphocytes have a T-helper phenotype with few suppressor CD8 + cells, indicating that these cells are actively involved in the pathogenesis of the lesions and in disease control. In the granuloma, the majority of macrophages stain for lysozyme which shows their secreting nature and the potentiality to release microbicidal products into the granuloma millieu 25,

High levels of TNF and angiotensin-converting enzyme have been documented in paracoccidioidomycosis patients 22, 23, 33 ; the local release of these products may be involved in the regulation of the granulomatous inflammation, as suggested for sarcoidosis, histoplasmosis and leprosy. It seems that in paracoccidioidomycosis, TNF may act as an immuno-modulator capable of enhancing and amplifying the immune response and promoting macrophage-mediated parasite killing 14, 33,

In the peripheral halo, there is a population of cells which stain for S-100 protein (APC). The presence of the APC in close association with the T-helper lymphocytes in the granuloma may favor the interplay between these cells with the release of T-cell stimulating factors, such as I12.

Lymphokines released by activated lymphocytes may attract, fix and activate macrophages at the inflammatory foci.
The activated macrophages may then show enhanced killing of P.
Brasiliensis, secrete cytokines and further differentiate into epithelioid cells 15, 25,
In addition, cytokines amplify the natural host defense against the parasite as documented by their ability to increase the fungicidal activity of neutrophils, which are cells frequently found around the fungal cells, at the center of the granuloma 15,

Fungal products may by themselves stimulate macrophages to secrete cytokines able to induce epithelioid cell transformation; these cells, however, in the absence of an immune response are less efficient in blocking the proliferation of the parasite 5, 24,

An epilhelioid cell-derived macrophage deactivating factor (ECD-MDF) has been recently described which exerts by a feedback mechanism a suppressive effect on the activated macrophage, the major effector cell of the immune system 21,
These findings demonstrate that macrophages can be modulated in two different directions of activity.

First, the well known cell activation process, which enhances the microbicidal and tumoricidal capacity of the cell. Second, they might be modulated to secrete factors which inhibit macrophage activation, controlling tissue healing on the one hand and facilitating persistence of agents in the tissues on the other 21,

Natural killer (NK) cells are another cellular component identified in the paracoccidioidal granuloma. They have been shown to limit the growth of P. brasiliensis in culture, suggesting that they may play a defensive role in paracoccidioidomycosis. Their cytotoxic activity is significantly lower in patients with paracoccidioidomycosis, a fact interpreted as an escape mechanism of the fungus 28,P.

brasiliensis granulomas are also characterized by a large number of IgG-secreting plasma cells at the periphery. In addition, IgG and C3 deposits on the P. brasiliensis cell wall are common findings within the granuloma, suggesting a participation of these humoral components in the blocking of antigenic diffusion and even of fungal survival 15, 25,

Trapping of fungal antigens inside macrophages in P.
Brasiliensis granulomas may also be demonstrated by immunohistochemical techniques, using an anti-P.
Brasiliensis antibody 15, 25,
Another approach to the study of the morphogenesis of the paracoccidioidal granuloma has been to look at the granuloma-inducing activity of chemical components of P.

brasiliensis cells. The intravenous inoculation of lipids extracted from yeast cells into mice, in the form of coated charcoal particles, induces an intense pulmonary granulomatous reaction around the particles. The active fractions were mainly composed of free fatty acids and triglycerides.

The data suggest that the formation of the granulomatous process may depend on the chemical composition of the agent which would attract and organize the macrophages around the parasitic cells 32, A similar study was carried out with the cell wall polysaccharides of yeast cells. The intravenous inoculation of an alkaline-soluble, acid-soluble fraction obtained after lipid extraction of yeast cell walls, induces an intense polymorphonuclear cell infiltrate in the lungs of mice at an early stage; later, the cellular infiltrate is composed predominantly of large, tightly packed mononuclear cells, with a tendency to organization and maturation to epithelioid cells.

In addition, the intraperitoneal inoculation of the fraction stimulates peritoneal macrophages, suggesting that the polysaccharide component might play an important role in paracoccidioidomycosis 2, 31, The presence of the lipid and polysaccharide components of the fungus due to multiplication of P.

Brasiliensis at the lesional sites provides elements for the understanding of some aspects of the inflammatory response observed in paracoccidioidomycosis, such as the neutrophil in-flux observed after fungal presentation and multiplication, the presence of suppuration in the center of the granuloma and the macrophage-rich exudate organized as epithelioid granulomas 2, 15, 31,

Further studies have investigated the granuloma-stimulating capacity of soluble P. brasiliensis components in animals with and without previous specific immunization. In immunized mice injected i.v. with bentonite particles coated with P. brasiliensis antigens, the inflammatory area around small pulmonary vessels is significantly greater than that in nonimmunized animals.

In addition, the inflammatory process evolves to fully developed epithelioid granulomas, as seen by electron microscopy which shows macrophages with characteristically interdigitated cytoplasmic borders.
This finding reinforces the importance of cellular immunity in the genesis of epithelioid granulomas in paracoccidioidomycosis 15,

Overall, the approach to the understanding of P. brasiliensis granulomas has considered either T-lymphocytes or macrophages as the pivotal cells in the morphogenesis of the inflammatory process. It is more likely that both cells individually and synergistically play an important role in the development of the granulomas through the release of inflammatory mediators that activate mechanisms of host defense against the parasite.

ROLE OF THE IMMUNE RESPONSE IN GRANULOMA FORMATION A primary role of CMI in granuloma formation has been emphasized in the literature.
However, insoluble antigen antibody complexes are able to produce granulomatous inflammation under experimental conditions 35,
Moreover suppurative granulomas, a distinctive form of inflammatory tissue reaction, found in various infectious processes such as cat-scratch disease, lympho-granuloma venereum, atypical tuberculosis, Yersinia lymphadenitis and tularemia, maintain a close relation-ship with B-lymphocytes; local secretion of specific immunoglobulins may occur, with subsequent formation of immune complexes which may recruit neutrophils via complement activation 13,

It has been suggested that during an early phase of the suppurative granuloma formation there is a initial phase of T-cell-mediated immune response. Abnormalities in the immune reaction might be associated with the development of a T-independent, macrophage-mediated immune response resulting in the recruitment and activation of monocytoid B cells within the granulomas 13,

Similar events may take place in immunosupressed patients; the predominance of a humoral response with the formation of insoluble antigen-antibody complexes may be the basis for the incomplete granulomatous response seen in these patients and also occasionally in athymic mice. The experimental immunopathogenesis of S.

japonicum egg granulomas may differ, at least in its earlier events, from that of S. mansoni.S. japonicum eggs are produced in large aggregates, while S. mansoni eggs enter the tissues singly. The lesions in schistosomiasis japonica are made up of eosinophilic abscesses, which appear soon after egg-laying; necrosis and plasma cell infiltration are seen both in the granulomas and in the periportal inflammation 38,

Recent data 19 have shown an Arthus type hypersensitivity, which is a complement mediated response, and an immediate type of hyper-sensitivity which is an interleukin-4-induced reaction, occurring early in S. japonica egg granulomas; these reactions may be related to eosinophil accumulation, necrosis and plasma cell infiltration.

Later a strong CMI reaction appears, which corresponds to the granuloma and fibrotic stages. Moreover, it has been demonstrated that the cellular components participating in egg-granuloma formation differ greatly according to the tissues involved 19,

In conclusion, it appears that the immunopa-thogenesis of the high-turnover granuloma is not unique.
Host and parasite factors interact in order to stimulate either a CMI or an antigen-antibody insoluble complex immunopathogenesis.
Failure of the CMI system may change the way high-turnover granulomas are formed.

In many epithelioid granulomas, the associated local humoral response is possibly important as a defense mechanism ( Fig.2 ). GRANULOMA NECROSIS AND FIBROSIS Granulomatous inflammation frequently results in tissue damage during the active phase, due to local secretory products of macrophages and neutrophils.

Tuberculosis is a model of an immune-mediated high-turnover epithelioid granuloma which frequently presents extensive necrosis, usually at the center of the granuloma. Caseous necrosis in tuberculosis is regarded as having an immunological basis 11, In the early tuberculosis lesion, there is little cellular death or tissue necrosis.

The tubercle bacilli multiply within tissue macrophages in a state of symbiosis until the time when an immune response occurs. A clonally exuded T lymphocyte population then appears in response to specific antigens of the tubercle bacillus. Chemotactic cytokines for macrophages and lymphocytes are produced which lead to macrophage aggregation and local activation with phagocytosis and killing of bacilli.

Under experimental conditions, it appears that, in BCG-induced granulomas, antigen-specific CD4 + T cells and their products are needed for macrophages to acquire the mycobactericidal function that enables them to control the infection 26, CMI is therefore a favorable immunologic reaction for the host that appears when there is a low local concentration of antigen/s.

On the other hand, a high local concentration of antigen/s speeds up the accumulation and activation of lymphocytes and macrophages at the site of antigen deposition and may cause caseation and liquefaction 11, Liquefaction is due to lysis of protein, lipid and nucleic acid components of the caseum by hydrolytic enzymes of macrophages and granulocytes.

Liquefaction perpetuates the disease in humans since the liquefied caseum facilitates the dissemination of the disease 11,
In other parasitic granulomas where central necrosis is observed, like those of cutaneous leishmaniasis, probably similar pathogenetic mechanisms are responsible for the tissue damage 34,

However, factors other than CMI also produce necrosis. Substances like silica are toxic to macrophages and cause necrosis by leakage of lysosomal enzymes 1, Fibrosis is a common terminal event of the granulomatous inflammation. Non immunological, low turnover, foreign body type granulomas stimulate the least amount of collagen production.

On the other hand, in high turnover granulomas, in which CMI is of considerable importance, fibrogenesis is marked and probably related to a direct action of cytokines produced by cells of the granuloma, chiefly T lymphocytes and macrophages 8,
In schistosomal granuloma and in the ensuing portal connective tissue deposition, histological changes suggestive of collagen matrix degradation have been described 3 thus showing that fibrosis may be partially reversible.

ACKNOWLEDGEMENTS We are indebted to Prof. Mario Rubens Montenegro for revising the manuscript and for valuable scientific advice. The authors also wish to thank Miss Maria Elí P. de Castro for secretarial help. (1) University of S. Paulo, Medical School, Department of Pathology and Institute of Tropical Medicine, Sào Paulo, Brasil.

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What are the different types of granulomatous inflammation?

Clinico-Pathological Study of Cutaneous Granulomatous Lesions- a 5 yr Experience in a Tertiary Care Hospital in India Iran J Pathol.2016 Winter; 11(1): 54–60. PMCID: PMC4749196 1 Dept. of Pathology, College of Medicine and Sagore, Dutta Hospital.Kolkata, India Find articles by 1 Dept.

Of Pathology, College of Medicine and Sagore, Dutta Hospital.Kolkata, India Find articles by 2 Dept.
Of Pathology, Bankura Sammilani Medical College, Bankura, India Find articles by 2 Dept.
Of Pathology, Bankura Sammilani Medical College, Bankura, India Find articles by 3 Dept.
Of Pathology, NRS Medical College, Kolkata, India Find articles by 4 Dept.

of Pathology, Calcutta National Medical College, Kolkata. India Find articles by 1 Dept. of Pathology, College of Medicine and Sagore, Dutta Hospital.Kolkata, India 2 Dept. of Pathology, Bankura Sammilani Medical College, Bankura, India 3 Dept. of Pathology, NRS Medical College, Kolkata, India 4 Dept.

Of Pathology, Calcutta National Medical College, Kolkata.
India Corresponding Information: Dr Subrata Pal, Gobindanagar, PO- Kenduadihi, Dist- Bankura, West Bengal, India, PIN-722102.
Email: subr[email protected] Received 2014 Oct 28; Accepted 2015 Jan 15.
© 2016, IRANIAN JOURNAL OF PATHOLOGY This is an open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License, () which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Granulomatous dermatoses are common skin pathology, often need histopathological confirmation for diagnosis. Histologically six sub-types of granulomas found in granulomatous skin diseases- tuberculoid, sarcoidal, necrobiotic, suppurative, foreign body & histoid type.

The aims of the present study were clinico-pathological evaluation of granulomatous skin lesions and their etiological classification based on histopathological examination. It was a five years (Jan 2009- Dec 2013) retrospective study involving all the skin biopsies. Detailed clinical and histopathological features were analyzed and granulomatous skin lesions were categorized according to type of granuloma & etiology.

Special stains were used in few cases for diagnostic purpose. Among 1280 skin biopsies, 186 cases (14.53%) were granulomatous skin lesions with a ratio 1:24. In histopathological sub-typing, tuberculoid granuloma was most common type (126 cases, 67.74%).

Most common etiology of granuloma in the study was leprosy (107 cases, 57.52%).
Other etiologies were cutaneous tuberculosis, foreign body granulomas, fungal lesions, cutaneous leishmaniasis, sarcoidosis and granuloma annulare.
Histopathology is established as gold standard investigation for diagnosis, categorization and clinico-pathological correlation of granulomatous skin lesions.

Key Words: Granuloma, histopathology, skin biopsy Granulomatous skin lesions are distinctive pattern of chronic inflammatory response of skin due to reaction against various organic and inorganic antigens (, ). Granulomas are characterized by focal collection of epithelioid cells or histiocytes, admixed with variable number of leucocytes (especially mononuclear cells) and multinucleated giant cells.

Granulomatous reaction is a type IV hypersensitivity reaction evoked by poorly soluble reactive substances.
Six types of granulomatous skin lesions are identified according to cellular constituents and associated changes: 1) tuberculoid, 2) sarcoidal, 3) necrobiotic, 4) suppurative 5) foreign body and 6) histoid type granuloma (,).

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Incidence and prevalence of different types of granulomatous dermatitis depend on geographic location. Granulomatous skin lesions are common in eastern India. Many granulomatous skin lesions have identical histomorphology and conversely a single pathology can produce varied histological features ().

They often lead to diagnostic confusion among Dermatologist & Pathologist due to variable morphology. The present study was undertaken to determine the frequency and pattern of different granulomatous skin lesions and clinico-histopathological correlation of the lesions to reach correct etiological diagnosis.

The present study was a retrospective analysis of all skin biopsies of granulomatous skin lesions received in the Department of Pathology, Bankura Sammilani Medical College &Hospital (Bankura, India), over a period of five yr from Jan 2009 to Dec 2013.

Ethical clearance was obtained from institutional ethical committee before undertaking the study.
Written consents were taken from all patients included in the study.
Detailed history and clinical data were collected from patient’s treatment sheet as well as from hospital’s record section.
Dermatological diagnosis was done by dermatologists.

Skin biopsies were taken at Dermatology Department and specimens were sent to our histopathology laboratory for histopathological examination. The biopsy samples were undergone routine tissue processing and section cutting. All cases were stained with H&E stain and special stains (PAS, ZN stain, Giemsa, Fite-Faraco, and Reticulin) were applied as required.

Histopathological diagnoses of skin biopsies were done by us in our laboratory.
Only the histopathologically confirmed cases of granulomatous skin lesions were included in study group.
The cases of non-granulomatous dermatoses and inadequate samples were excluded from study.
All cases of granulomatous skin lesions were analyzed in respect to clinical information and histopathological examination of biopsy samples.

Data analysis was done by use of statistical software SPSS. In the five years retrospective study, total 1280 skin biopsies were evaluated. Granulomatous skin lesions were diagnosed in 186 cases (14.42%). Among 186 cases, 103 cases (55.38%) were male and 83 cases (44.62%) were female.


Age	Male	Female	Total	Percentage (%)
0-10	4	1	5	2.68
11-20	29	28	57	30.65
21-30	31	22	53	28.49
31-40	15	17	32	17.20
41-50	13	7	20	10.75
51-60	6	5	11	5.91
61-70	3	2	5	2.68
>70	2	1	3	1.61
Total	103	83	186	100

Histopathological sub types of granulomatous lesions revealed 126 cases (67.74%) were tuberculoid type granulomas. Distributions of different category of granulomatous lesions were exhibited in, Distribution of cases according to histopathological types of granuloma


Type of Granuloma	Number	)%( Percentage
Tuberculoid type	136	73.12
Foreign body type	12	6.45
Suppurative	09	4.84
Necrobiotic	23	12.37
Sarcoidal	03	1.61
Histiocytic	13	6.99
Total	186	100

On histopathological examination and etiological typing of lesions, leprosy was the most common type of diagnosis (107 cases, 57.52%). Among the leprosy cases borderline tuberculoid was the most common sub-groups (62 cases, 57.94%). The distributions of different sub-types of cases have been shown in,


Diseases	Number (n)	Percentage (%)
Leprosy -Tuberculoid -BT -BB -BL -Lepromatous -Indeterminate -Histoid	n- 1071462071013 01	57.52
Tuberculosis -Lupus vulgaris -Scrofuloderma -TVC	n- 462911 06	24.73
Foreign body granuloma -Epidermal cyst -Xanthoma -Rhinosporidiosis	n- 90602 01	4.84
Fungal infection -Actinomycosis -Maduromycosis -Pseudallescheria boydii	n- 70302 02	3.76
Sarcoidosis	n- 3	1.61
Cutaneous Leishmaniasis	n- 2	1.07
Granuloma annulare	n- 9	4.84
Helminthiasis	n- 2

Cutaneous tuberculosis was diagnosed in 46 cases (24.73%), among which lupus vulgaris was the most common sub-types (29 cases, 63.04%); scrofuloderma (11 cases, 23.91%), and tubercular verruca cutis (6 cases, 13.04%) comprised rest of the cases of cutaneous tuberculosis.

Among the 12 cases of foreign body granulomatous skin lesions, seven were epidermal cyst, three were xanthoma & cutaneous rhinosporidiosis was diagnosed in two cases. Among the 23 necrobiotic granulomatous lesions, 16 cases were tuberculous origin and seven cases were granuloma annulare. Histologically the cases of granuloma annulare show necrobiosis and palisaded granuloma with peripheral deposition of collagen mixed with lymphocytes, histiocytes and fibroblasts.

Seven cases out of nine granuloma annulare were solitary lesion over extensor surface of extremities with female preponderance. We diagnosed seven cases of fungal granuloma in our study. All the fungal skin lesions showed suppurative granuloma. Three cases were diagnosed as actinomycosis and diagnosis was confirmed by gram stain.

Maduromycosis and Pseudallescheria boydii were diagnosed in two cases each. Three cases of sarcoidosis and two cases of cutaneous leishmaniasis were diagnosed in the present study. Most of the histiocytic granulomas in our study were lepromatous leprosy (11 cases out of 13, 84.61%). Granulomatous inflammation is a type-IV hypersensitivity reaction to an antigen.

Various infectious and non-infectious granulomatous dermatoses are frequent among the population of eastern part of India. Definitive etiological diagnosis is important for their management. Histopathology is a gold standard tool for correct diagnosis of various granulomatous skin lesions.

Microscopically, wide spectrum of histopathological features of different granulomatous lesions was observed in the present study.
We classified the lesions based on histo-morphology and etiology of the granulomatous diseases.
In this study, we found male preponderance (103 cases among 186) with a sex ratio of 1.24.

Our findings agreed with previous studies (,, ), but not with Zafar et al. (). Large number of cases in the present study were among 11-20 yr. (57 cases, 30.65%) and 21-30 yr. (53 cases, 28.49%); consistent with the findings of Pawale et al. (). In the present study, largest group of lesions were tuberculoid granulomas (136 cases, 73.12%).

Similar findings were seen in previous studies with the amount of 77.3% (, ), and 87.7% (). (Majority of the cases in the present study were leprosy (107 cases, 57.62%). Our findings wereconsistent with Pawale et al. () (56.6%) but incidence of leprosy was lower than the others, 79.7%and 72.4% (, ). We classified the leprosy cases according to Ridley and Jopling classification.

The largest subgroup of leprosy in our study was borderline tuberculoid (62 cases, 57.94%) similar to the findings of Gautam et al. (46.7%) and Bal et al. (55.2%)(,). All the tuberculoid leprosy and most of the borderline tuberculoid cases were similar to non-caseating granulomas of tuberculosis and sarcoidosis (,).

Modified ZN stain revealed lepra bacilli only in seven cases of borderline tuberculoid leprosy and in none of the tuberculoid leprosy. Location of the granulomas around the neurovascular bundles and involvement of arrector pili muscle and adnexa in the background of proper clinical presentation cues to diagnose tuberculoid and borderline tuberculoid leprosy ().

However, most of the borderline lepromatous (BL) and all the lepromatous leprosy (LL) cases exhibit histiocytic granulomas (), and were strongly positive for lepra bacilli in modified Z-N stain. Lepra bacilli were seen in 30 cases (14 cases of lepromatous leprosy, six borderline lepromatous, seven cases of borderline tuberculoid, two cases of erythema nodosum leprosum and one case of histoid leprosy), 28.03% of all the leprosy cases.

Bal et al. found AFB in 36.4% of their cases, slightly higher than our study (). Tuberculosis was the second most common cause of granulomatous skin lesions in our study, accounting 24.73% of all the granulomatous skin lesions. Incidence of cutaneous tuberculosis in the present study (3.59% of all the skin biopsies) is higher than the worldwide incidence (0.1 to 1% of all cutaneous lesions) (,, ).

The incidence of cutaneous tuberculosis has been found as 3.7% in Pakistan (). Possible reasons of higher incidence of cutaneous tuberculosis in our study were poor nutrition and poverty, poor personnel hygiene in the tribal population of the district.

Cutaneous tuberculosis was more prevalent in female than male (1.3:1) in the present study, supporting the finding of prevoious studies (,,, ).
Lupus vulgaris () was the most common type of cutaneous tuberculosis in our study (29 cases, 63.04%) similar to the previous investigations (,).
But few other studies revealed scrofuloderma as the commonest type of lesion, particularly in childhood (,).

However, in the present study scrofuloderma was diagnosed in 11 cases (23.91%); 2 nd common tubercular skin lesion. Twelve cases (6.45%) of foreign body type granuloma were identified in the present study. Most common type foreign body granuloma was epidermal cyst (six cases), correlating the findings of Gautam et al.

Granulomatous reaction occurs against the rupture keratin material of epidermal cyst resulting in numerous multinucleated giant cells and keratin granuloma formation surrounding the cyst wall ().
Cutaneous xanthoma was diagnosed in two cases; where histopathology revealed aggregates of foamy histiocytes and touton giant cells and cholesterol clefts.

Another study by Pawale et al. found cutaneous xanthoma as the most common type foreign body type cutaneous granulomatous lesions (). We found two cases of cutaneous rhinosporidiosis in the present study, both the cases were young male patients, had nodular skin lesion at neck region.

Extra-nasal rhinosporidiosis is common at ocular and head neck region and present as nodular skin lesions with granular reddish surface (). Granuloma formation and giant cells are very common inflammatory reaction against the chettenious wall of sporangium and spores () (). We diagnosed seven cases (3.76%) of fungal cutaneous granuloma in the present study.

Our observation is similar to other studies with the amount of 3.2% and 3.3% (,). Pawale et al. found 11.32% fungal lesions in their study (). Distribution of the fungal lesions in the present study was mostly on the extremities over chest wall. Three cases were actinomycetes, two cases were maduromycosis and P.

Boydii was diagnosed in another two cases.
Cutaneous leishmaniasis was diagnosed in two cases (1.07%) in our series.
Incidence varies in different tropical areas like (1.16%) in the study by Bal et al., whereas Qureshi R et al found 56.7% in Pakistan (,).
Our findings are consistent with other studies in India (1.16%) ().

Both the cases of cutaneous leishmaniasis were male and presented with itchy nodulo-ulcerated skin lesions at upper extremities and face. Microscopy of cutaneous leishmaniasis revealed heavy plasma cell infiltration at sub epithelial tissue and macrophages containing amastigate forms in case of early lesions ().

Leishman Donovan (LD) bodies were demonstrable in both the cases in our study. Bal et al. found LD bodies in 50% of the leishmaniasis cases in their series (). Leishmania skin test and staining of the exudates by Giemsa & Wrights stain are the ancillary tests for diagnosis (). We diagnosed two cases of cutaneous sarcoidosis in the present study.

Both the cases exhibited non-caseating epithelioid granuloma devoid of inflammatory cells and Langhans giant cells. Incidence of sarcoidal lesions in the present study was 1.07%, quite similar to Gautam et al. (1.88%) (). Both the cases in our study were female and diagnosis also correlated with the findings of chest x-ray and serum calcium level.

Granuloma annulare was diagnosed in nine cases (4.83%) in our series.
Gautam K et al, Pawale J et al and Qureshi R et al found 3.7%, 3.77% and 5.4% respectively (-).
Our findings were consistent with the previous studies.
Most of the cases were young female and seven cases showed localized lesions on dorsal aspect of extremities similar to findings of other authors (, ).

However, Mohan H et al found male preponderance in their series (). All the granulomatous skin lesions were correlated with clinical history, examination findings and ancillary investigations. Histopathology is gold standard for diagnosis & categorization of granulomatous skin lesions.

Our study gives a prevalence of important granulomatous skin diseases in this region, which will help in implicating health programmes and management of the individual cases. The authors declare that there is no conflict of interests.1. Gautam K, Pai RR, Bhat S. Granulomatous lesions of the skin. Journal of Pathology of Nepal.2011; 1 (2):81–6.2.

Pawale J, Belagatti SL, Naidu V, Kulkarni MH, Puranik R. Histopathogical study of cutaneous granuloma. Ind J Public Health Res Develop.2011 Jul; 2 (2):74–9.3. Qureshi R, Sheikh RA, Haque AU. Chronic granulomatous inflammatory disorders of skin. Int J Pathol.2004; 2 (1):31–4.4.

Zafar MNU, Sadiq S, Menon MA. Morphological study of different granulomatous lesions of the skin. J Pak Assoc Dermatol.2008; 18 (1):21–8.5. R Singh, K Bharathi, R Bhat, C Udayashankar. The histopathological profile of non-neoplasticdermatological disorders with special reference to granulomatous lesions – study at a tertiary care centre in pondicherry.

Internet J Pathol.2012; 13 (3):14240.6. Dhar S, Dhar S. Histopathological features of granulomatous skin diseases: an analysis of 22 skin biopsies. Indian J Dermatol.2002; 47 (2):88–90.7. Bal A, Mohan H, Dhami GP. Infectious granulomatous dermatitis: a clinico-pathological study.

Indian J Dermatol.2006; 51 (3):217–20.8.
Hirsh BC, Johnson WC.
Concepts of granulomatous inflammation.
Int J Dermatol.1984 Mar; 24 (2):90–9.9.
Young RJ 3rd, Gilson RT, Yanase D, Elston DM.
Cutaneous sarcoidosis.
Int J Dermatol.2001 Apr; 40 (4):249–53.10.
Han Y, Anwar J, Iqbal P, Kumar A.
Cutaneous tuberculosis: a study of ten cases.

J Pak Asso Dermatol.2001; 11 (3):6–10.11. Yasmeen H, Kanjee A. Cutaneous tuberculosis: a three year prospective study. J Pak Med Assoc.2005 Jan; 55 (1):10–2.12. Kumar B, Muralidhar S. Cutaneous tuberculosis: a twenty year prospective study. Int J Tuberc Lung Dis.1999 Jun; 3 (6):494–500.13.

Puri N et al. A clinical and histopathological profile of patients with cutaneous tuberculosis. Int J Dermatol.2011; 56 (5):550–2.14. Farina MC, Gegundez MI, Pique E et al. Cutaneous tuberculosis: a clinical, histological and bacteriologic study. J Am Acad Dermatol.1995 Sep; 33 (3):433–40.15. Kumar B, Rai R, Kaur I, Sahoo B, Muralidhar S, Radotra BD.

Childhood cutaneous tuberculosis: a study over 25 years from northern India. Int J Dermatol.2001; 40 (1):26–32.16. Saha J, Basu AJ, Sen I, Sinha R, Bhandari AK, Mondal S. Atypical presentation of rhinosporidiosis: A clinical dilemma? Indian J Otolaryngol Head Neck Surg.2011 Jul; 63 (3):243–6.17.

What is the pathogenesis of granulomas?

Resident cells initiate an immune response after exposure to antigen. These include mast cells, resident histiocytes, and γδT cells, which produce tumor necrosis factor (TNF) and interferon (IFN)-γ to recruit circulating monocytes and neutrophils.

What are the two types of granulomas?

Most granulomas fall into one of two categories: caseating, with a necrotic center, or non-caseating, without any necrosis. Caseating granulomas are often caused by infections, while the non-caseating type is typically caused by an inflammatory condition.

What are four granulomatous diseases?

Granulomatosis with polyangiitis (Wegener granulomatosis) – Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a disease that typically consists of a triad of airway necrotizing granulomas, systemic vasculitis, and focal glomerulonephritis.

If the disease does not involve the kidneys, it is called limited granulomatosis with polyangiitis.
Although the cause of granulomatosis with polyangiitis is still not certain, it is believed to most likely have an autoimmune etiology.
Symptoms Granulomatosis with polyangiitis most commonly occurs in whites during the third to fifth decades of life.

Often, the patient initially presents with symptoms that involve the head and neck. Inflamed, friable mucosa; ulcerations; septal perforations; and saddle nose deformities may be seen on nasal examination; therefore, the patient may present with various nasal symptoms, including chronic nasal congestion, epistaxis, and pain.

The patient may also present with laryngeal symptoms (wheezing), ear symptoms (otitis media), and oral ulcerations. Pulmonary symptoms include cough and hemoptysis. A mismatch often occurs in the severity of the symptoms and the relatively benign appearance of the lesions. With regard to cutaneous lesions, a study by Montero-Vilchez et al found that out of 21 patients with granulomatosis with polyangiitis, the chief sites of these were the lower limbs (57.14%) and the face (23.81%).

Laboratory examination Laboratory evaluation includes elevated inflammatory indicators, such as C-reactive protein and erythrocyte sedimentation rate (ESR). An elevated classic antineutrophil cytoplasmic antibody (C-ANCA) level is 80% specific for granulomatosis with polyangiitis.

In disseminated disease, 78-100% sensitivity is reported, whereas in upper airway disease, 60-70% sensitivity is reported. Histologic examination reveals granulomatous change consisting of macrophages and accompanying inflammatory cells and giant cells. A characteristic patchy necrosis surrounded by giant cells through the tissue is often present.

The vasculitis reveals granulomatous inflammation to the vessel wall in small and medium-sized arteries and veins, making granulomatosis with polyangiitis a true vasculitis. Other features that may be noted on histopathologic examination include microabscess formation and cicatricial scarring.

Treatment Treatment includes steroids for 4-6 weeks until the disease is controlled.
Steroids are then tapered over 6 months.
Cyclophosphamide is an alkylating chemotherapeutic agent that can be tapered to a maintenance dose.
Trimethoprim-sulfamethoxazole has also demonstrated early promise.
A study by Puéchal et al indicated that azathioprine and methotrexate have comparable efficacy in maintaining remission in granulomatosis with polyangiitis.

The 10-year overall survival rate for patients receiving azathioprine was 75.1%, compared with 79.9% for those receiving methotrexate, while the relapse-free survival rate was 26.3% for patients receiving azathioprine, compared with 33.5% for those receiving methotrexate.

A study by Springer et al indicated that discontinuation of or use of low drug dosages in maintenance therapy increases the risk of relapse in granulomatosis with polyangiitis.
The study involved 157 patients with the disease who, after achieving remission, underwent maintenance therapy with methotrexate or azathioprine; they were followed up for a median period of 3.1 years.

In patients who received maintenance medication for more than 18 months, the hazard ratio (HR) for relapse was reduced by 29%, while in those who continued maintenance treatment for more than 36 months, the HR for relapse was reduced by 66%. Fifty-two percent of relapses took place in patients who were no longer on maintenance therapy.

Among patients on methotrexate, 52% who relapsed during therapy were receiving less than 15 mg per week, while among those on azathioprine, 67% of those who relapsed during treatment were receiving 50 mg or less per day.
Repeated inflammatory insult in granulomatosis with polyangiitis leads to focal areas of scarring and fibrotic damage to airway structures.

Only 20% of cases of subglottic stenosis due to the disease will resolve with immunotherapy. Therefore, laser treatment, tracheal resection and anastomosis, and tracheotomy are treatment options for subglottic stenosis secondary to granulomatosis with polyangiitis.

What cytokines make granulomas?

Abstract – Granulomas are a local formation of specific cells including macrophages and lymphocytes revealing a chronic inflammatory reaction against infection, often due to intracellular agents. Granulomas can be composed of macrophages (foreign body reaction), epithelioid cells (immune granulomas of sarcoidosis, tuberculosis), or Langerhans’ cells (histiocytosis X).

In immune granulomas, the epithelioid cells derived from activated macrophages are found at the centre of the granuloma associated with CD4+ T-lymphocytes, while the periphery is mainly populated with CD8+ T-lymphocytes. Granulomas are not static formations, the rate of cell turnover is high. Different cytokines have been identified as mediators involved in the formation and maintenance of these granulomas: IL2, interferon gamma, TNF alpha, 1,25(OH)2D3, IL1.

Major questions, especially concerning antigens involved in granulomatous reactions, remain to be answered for a better understanding of these events.

What is the significance of granulomatous inflammation?

These cells are aggregated into well demarcated focal lesions and the designation granuloma (granule + oma = tumor) derives from this peculiar aspect.
In addition, granulomas usually contain an admixture of other cells, especially lymphocytes and plasma cells, and, depending on their stage, fibroblasts 39,

The turnover time in most instances is about one to two weeks 27,
The production of monocytes is under feedback control; peripheral macrophages and lymphocytes secrete factors that have both stimulatory and inhibitory actions on stem cell proliferation in the bone marrow.
Although exudation seems to be by far the most important source of macrophages in the inflammatory reaction, local histiocytic proliferation does occur 1, 39,

TYPES OF GRANULOMA Granulomas fall into two groups, namely foreign body or low turnover cell and epithelioid, hyper-sensitivity 12 or high turnover cell types 38, An inducing agent is often recognizable in foreign body granulomas, usually phagocytosed by macrophages and foreign body giant cells. The foreign body granuloma is a poorly organized granuloma with focal aggregates of macrophages intermixed with few lymphocytes and plasma cells.

Granulomatogenic agents, although poorly degradable, are relatively inert and nontoxic to the cells. Immune mechanisms are of minor importance in the pathogenesis of foreign body granulomas which may be regarded as “phagocytic granulomas”. Macrophages and foreign body giant cell are frequently seen apposed to the inducing agent which is often observed internalized by the giant cell.

Both cells originate from fusion of macrophages rather than nuclear division and probably result from the attempt of two or more macrophages to phagocytose a single particle, which results in the fusion of their plasma membranes. Foreign body giant cells mature into Langhans cells, probably by movements of the intracellular cytoskeleton 1,

The distribution of the cytoskeletal components of these cells may be characteristic of free wandering cells since it is seen in other free cells such as polymorphonuclear leukocytes and fibroblasts 6,
At least one cytokine, the monocyte chemo-attractant protein 1 (MCP-1), which is released by monocytes following phagocytosis 18, may be involved in the foreign body granuloma formation.

In these granulomas a high rate of recruitment and local division of macrophages are observed to compensate for the relatively short life span (usually only a few days) and high death rate of these cells within the lesion 1,
The causative agent, when present, is detected only in a small proportion of phagocytic cells, usually at the center of the granuloma.

They originate from macrophage precursors and have an elongated euchromatin nucleus, conspicuous nucleoli and an abudant cytoplasm with prominent endoplasmic reticulum and few lysosomes. The cells appear to be closely associated, and are interlocked by pseudopods in zipper-like arrays but with no junctional specialization.

At an early stage, epithelioid granulomas show an admixture of macrophages, few epithelioid cells and lymphocytes. Lymphocytes at the center of the granuloma are mostly CD4 (helper-inducer) T lymphocytes 29, When the granuloma matures, a halo of B and chiefly CD8 (suppressor-cytotoxic) T lymphocytes is observed at the periphery together with fibroblasts.

IMMUNOPATHOGENESIS OF THE SCHISTOSOMAL GRANULOMA Among the experimental and human epithelioid granulomas, the immunopathogenesis of the schistosomal granuloma is one of the best studied.
Schistosomiasis mansoni represents the first form of granulomatous inflammation that has been clearly shown to be of immunological origin 7, 8, 38,

The probable events leading to the schistosomal egg granuloma begin with antigen-presenting cells (APC), mostly macrophages, expressing major histocompatibility (MHC) class II antigens, interacting with T lymphocytes with production of cytokines.
At this stage gamma-interferon (gamma-IFN) appears to up-regulate the MHC class II display on APC and the induction of cytokines such as interleukin 1 (I11) and tumor necrosis factor (TNF) production by macrophages 20,

In the schistosomal granuloma, eosinophils may be part of the CMI reaction and their depletion delays egg destruction. Stimulated macrophages evolve to epithelioid and giant cells. Lymphocytes and plasma cells form a halo surrounding the granuloma. Different degrees of collagen synthesis due to an interaction of macrophages and lymphocytes with fibroblasts may also be seen at the periphery of the granuloma 7, 8,

As the granuloma matures, antigen/s become restricted to the miracidium and immunoglobulins, chiefly of the IgG class, are detected at the periphery, corresponding to the inflammatory halo, where immunoglobulin-producing cells are observed.
Epithelioid cells act as a barrier between antigens at the center and antibodies produced by B lymphocytes in the peripheral inflammatory halo; therefore these cells play a critical role in the granulomatous inflammation.

The small antigen-antibody complexes formed may be removed by local macrophages 9, 10 ( Fig.1 ). Though the deleterious role of the granulomatous inflammation, through the secretion of tissue-destructive substances by its cell population, has been extensively studied 8, it now appears that granuloma formation is intrinsically favorable to the host.

BRASILIENSIS GRANULOMA The P. brasiliensis granuloma is generally centered around one or more fungal cells and is composed of giant cells and epithelioid cells; therefore it is an epithelioid granuloma. Polymorphonuclear leukocytes may be observed close to the fungi in the central area; encircling the granuloma, there is a halo of mononuclear cells.

Paracoccidioidomycosis presents two polar clinical forms, namely the hyperergic pole which is characterized by localized infection, persistent cellular immune response and a compact epithelioid granuloma, and the anergic pole which is represented by disseminated infection, decreased cellular immunity and loose, parasite-rich, granulomatous inflammation.

The microanatomy of P.
Brasiliensis granulomas has been investigated by the use of immunohistochemical techniques and monoclonal antibodies to T-lymphocyte subsets.P.
Brasiliensis granulomas, both in patients and in experimentally infected mice, show a T-cell peripheral mantle around central aggregates of macrophages.

High levels of TNF and angiotensin-converting enzyme have been documented in paracoccidioidomycosis patients 22, 23, 33 ; the local release of these products may be involved in the regulation of the granulomatous inflammation, as suggested for sarcoidosis, histoplasmosis and leprosy.
It seems that in paracoccidioidomycosis, TNF may act as an immuno-modulator capable of enhancing and amplifying the immune response and promoting macrophage-mediated parasite killing 14, 33,

Lymphokines released by activated lymphocytes may attract, fix and activate macrophages at the inflammatory foci.
The activated macrophages may then show enhanced killing of P.
Brasiliensis, secrete cytokines and further differentiate into epithelioid cells 15, 25,
In addition, cytokines amplify the natural host defense against the parasite as documented by their ability to increase the fungicidal activity of neutrophils, which are cells frequently found around the fungal cells, at the center of the granuloma 15,

An epilhelioid cell-derived macrophage deactivating factor (ECD-MDF) has been recently described which exerts by a feedback mechanism a suppressive effect on the activated macrophage, the major effector cell of the immune system 21, These findings demonstrate that macrophages can be modulated in two different directions of activity.

Natural killer (NK) cells are another cellular component identified in the paracoccidioidal granuloma.
They have been shown to limit the growth of P.
Brasiliensis in culture, suggesting that they may play a defensive role in paracoccidioidomycosis.
Their cytotoxic activity is significantly lower in patients with paracoccidioidomycosis, a fact interpreted as an escape mechanism of the fungus 28,P.

Trapping of fungal antigens inside macrophages in P.
Brasiliensis granulomas may also be demonstrated by immunohistochemical techniques, using an anti-P.
Brasiliensis antibody 15, 25,
Another approach to the study of the morphogenesis of the paracoccidioidal granuloma has been to look at the granuloma-inducing activity of chemical components of P.

The data suggest that the formation of the granulomatous process may depend on the chemical composition of the agent which would attract and organize the macrophages around the parasitic cells 32,
A similar study was carried out with the cell wall polysaccharides of yeast cells.
The intravenous inoculation of an alkaline-soluble, acid-soluble fraction obtained after lipid extraction of yeast cell walls, induces an intense polymorphonuclear cell infiltrate in the lungs of mice at an early stage; later, the cellular infiltrate is composed predominantly of large, tightly packed mononuclear cells, with a tendency to organization and maturation to epithelioid cells.

brasiliensis at the lesional sites provides elements for the understanding of some aspects of the inflammatory response observed in paracoccidioidomycosis, such as the neutrophil in-flux observed after fungal presentation and multiplication, the presence of suppuration in the center of the granuloma and the macrophage-rich exudate organized as epithelioid granulomas 2, 15, 31,

In addition, the inflammatory process evolves to fully developed epithelioid granulomas, as seen by electron microscopy which shows macrophages with characteristically interdigitated cytoplasmic borders.
This finding reinforces the importance of cellular immunity in the genesis of epithelioid granulomas in paracoccidioidomycosis 15,

ROLE OF THE IMMUNE RESPONSE IN GRANULOMA FORMATION A primary role of CMI in granuloma formation has been emphasized in the literature.
However, insoluble antigen antibody complexes are able to produce granulomatous inflammation under experimental conditions 35,
Moreover suppurative granulomas, a distinctive form of inflammatory tissue reaction, found in various infectious processes such as cat-scratch disease, lympho-granuloma venereum, atypical tuberculosis, Yersinia lymphadenitis and tularemia, maintain a close relation-ship with B-lymphocytes; local secretion of specific immunoglobulins may occur, with subsequent formation of immune complexes which may recruit neutrophils via complement activation 13,

Recent data 19 have shown an Arthus type hypersensitivity, which is a complement mediated response, and an immediate type of hyper-sensitivity which is an interleukin-4-induced reaction, occurring early in S. japonica egg granulomas; these reactions may be related to eosinophil accumulation, necrosis and plasma cell infiltration.

In conclusion, it appears that the immunopa-thogenesis of the high-turnover granuloma is not unique. Host and parasite factors interact in order to stimulate either a CMI or an antigen-antibody insoluble complex immunopathogenesis. Failure of the CMI system may change the way high-turnover granulomas are formed.

Tuberculosis is a model of an immune-mediated high-turnover epithelioid granuloma which frequently presents extensive necrosis, usually at the center of the granuloma.
Caseous necrosis in tuberculosis is regarded as having an immunological basis 11,
In the early tuberculosis lesion, there is little cellular death or tissue necrosis.

Under experimental conditions, it appears that, in BCG-induced granulomas, antigen-specific CD4 + T cells and their products are needed for macrophages to acquire the mycobactericidal function that enables them to control the infection 26,
CMI is therefore a favorable immunologic reaction for the host that appears when there is a low local concentration of antigen/s.

Liquefaction perpetuates the disease in humans since the liquefied caseum facilitates the dissemination of the disease 11,
In other parasitic granulomas where central necrosis is observed, like those of cutaneous leishmaniasis, probably similar pathogenetic mechanisms are responsible for the tissue damage 34,

On the other hand, in high turnover granulomas, in which CMI is of considerable importance, fibrogenesis is marked and probably related to a direct action of cytokines produced by cells of the granuloma, chiefly T lymphocytes and macrophages 8, In schistosomal granuloma and in the ensuing portal connective tissue deposition, histological changes suggestive of collagen matrix degradation have been described 3 thus showing that fibrosis may be partially reversible.

What is the difference between granulomatous and non granulomatous inflammation?

eye inflammation –

What is the meaning of granulomatous?

Overview – Chronic granulomatous (gran-u-LOM-uh-tus) disease (CGD) is an inherited disorder that occurs when a type of white blood cell, called a phagocyte, doesn’t work properly. Phagocytes usually help your body fight infections. When they don’t work as they should, phagocytes can’t protect your body from bacterial and fungal infections.

Chukwudi Eze