Review Article Biology and Medicine, 1 (3): Rev1, 2009

eISSN: 09748369, www.biolmedonline.com

Does intrinsic immune defect against common microbial pathogens play an important role in arthritic manifestation?

*S Subramanian, S Dhivya Department of Biotechnology, International Research Institute for the Deaf (IRID), An Institute under Acoustical Foundation for Education and Charitable Trust (AFECT), Chennai, India.

*Corresponding author: [email protected]

Abstract The autoimmune diseases are characterized by inflammation and resulting degradation of macromolecules of specific foci. Etiopathogenesis of arthritis is still unclear. In recent times many studies have been published, giving satisfactory explanation of infection and defective immune mechanisms for arthritic etio-pathogenesis. Understanding etio-pathogenesis is the most important and fundamental aspect of any particular problem. Many have given their different views on the above to educate the society. Out of these views, very few clear views were brought to the notice on immune dysfunction to common microbial infections. Convincingly, the above may have a strong connection to the disorder. Generally, it is thought that common microbial infections cause known problems but in unforeseen situation the dysregulation of immune function may also have acceptable reason behind the etio-pathogenesis. Vice-versa, defective immune functions like defective B cell function, defective B Cell Receptor signaling mechanism, dysregulated function, auto-antibodies’ cross reactivity to self antigens, inappropriate complement cascade events and defective apoptosis are few privileged environments which are discussed here for possible explanation of etiology of rheumatoid arthritis. This review deals with infection connection and defective immune mechanism of rheumatoid manifestation for further better understanding of etiopathogenesis.

Keywords: Autoimmunity; Arthritis; Inflammation; Defective immune response; Common microbial pathogens.

Introduction are thought to participate in chronic Etiology for rheumatoid arthritis hypothesized inflammatory joint disease. These immune it could be an infectious disease and possibly responses may reflect either a normal of other conditions as many as endocrine, response to usual antigenic stimulation or to a psychosomatic, hereditary and defective regulatory dysfunction or both. Similarly, apoptosis (Cutolo, 1997; Pittoni, 2002) etc., individuals with primary or acquired Many suggested mechanisms to etiology of immunodeficiency has increased incidence of the disease is still believed relevant to the autoimmunity. This classified as disorders of manifestation, particularly infectious cell-mediated immunity, humoral immunity, connection posted for etiopathology gives phagocyte cell function, and the complement satisfactory explanation. Similarly system (Barrett and Sleasman 1990). Several inflammatory joint disease may develop antibody deficiencies are also found following an extra-articular infection. The associated with autoimmune diseases. complex interactions between the triggering Combined cellular and antibody deficiencies, microbe and the defense mechanisms of the such as Wiskott-Aldrich syndrome, carry an host in arthritis have been studied in several increased risk for juvenile rheumatoid arthritis. laboratories around the world, and interesting Concomitantly immunologic defect in observations has been made. The eliminating microbial antigens resulting in demonstration of antigens of an infective agent chronic immunologic predispose to at specific foci in association with a specific both autoimmunity and immunodeficiency. local immune response suggests the Defects within one component of the immune pathogenetic importance of the agent. In system may alter the way a pathogen-induced addition to microbial candidates, defective immune response and lead to inappropriate immune arm connection giving satisfactory immune response. explanation to etiology. Some of the common Immunodeficiency commonly proceed microbial candidates and defective immune to development of autoimmunity, it is possible function against common microbes has been that immunodeficient state renders individuals tabled (tab 1&2). more susceptible to infectious agents, which Both humoral and cell mediated then trigger an autoimmune condition. This immune responses against common microbes hypothesis could be applied to the association

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 of autoimmunity with many inflammatory inflammatory stimuli may be an additional diseases of autoimmune origin. Another factor in the pathogenesis of RA (Chikanza et possibility is that, chronic infection resulted al., 1992). Furthermore, immunological failure in clearing circulating immune mechanisms to the tissue damage caused by complexes may leads to autoimmunity through the initial inflammatory reactions play a central immune complex deposition in the tissues. role in the etiopathogenesis, because findings These mechanisms may play important role in in chronic RA suggest a defective down- the development of autoimmune diseases in regulation of the immune response. On the patients with complement deficiencies. above understanding the immunologic defects Deficiencies of the complement system to that contribute to the development of systemic lupus erythematosus (SLE), autoimmunity will provide an insight into the glomerulonephritis, vasculitis and abnormal pathogenesis of the autoimmune process.

Table 1. List of intrinsic defect to rheumatoid arthritis

T cell Function Disease Abnormal clonal expression and suppressed proliferation RA Dysfunctional effect on the regulation of autoantibodies SLE B cell Defective B cell antigenic stimulation Hypogammaglobulinemia Dysregulaton of B cell homeostasis associated to B cell stimulation RA Quantitative and Qualitative defect in dentritic cell RA and SLE Defective apoptosis promoted survival of autoreactive cells Ra and SLE

Table 2. List of intrinsic defect in RA to microbial antigen

T cell Function Disease Organism Qualitative reduction of T cells AS K. pneumonia Quantitative reduction of synovial T cells RA Microbial glycolipids Defective suppressor T cells function RA/SLE EBV T cell IL-12 deficiency CNS Pathology Semliki Forest Virus Functionally defective Fc(IgG)+ T cell SLE Retroviral B cell Downstream B cell signaling pathway SLE Microbial LPS Autoreactive B cell defective tolerance checkpoint SLE Microbial LPS Class switch-defect RA Parvovirus B 19 Defective B cell function RA/SLE EBV Defective antibody regulation RA Parvovirus B 19 CSF TNF deficiency relate to reduced expression of IgE RA/SLE in vitro study receptor IFN deficiency relate to decreased IgM, B cell, RA/SLE In vitro study Macrophage and Granulocytes function Complements C1q deficiency associated defective apoptosis RA/SLE/Crohn’s Neisseria meningitides disease/SS Streptococcus pneumonia Terminal complement component deficiency Raynaud’s phenomena MMPs MMP - 9 deficiency RA Staphylococcus sp. MMP – 7 deficiency Allograft rejection Viral sp. Fas defective MRL-mice RA Staphylococcus sp. Mycoplasma sp. Depressed phagocytic activity RA/SLE Mycoplasma sp. Defective apoptosis associated CTL activity RA Mycobacterium sp.

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Review Article Biology and Medicine, 1 (3): Rev1, 2009

T cells tolerance and resistance against adjuvant Diagnosis of arthritis using various laboratory arthritis speculates importance of T cell methods identified microbe-specific T- regulatory mechanism (Gaston, 1989; lymphocytes and its lymphokines in Wegner, 2005; Skapenko, 2005). Hence autoimmune diseases speculate importance of defective regulatory immune mechanism might the infectious connection to the above allow the breakdown of peripheral tolerance, manifestation. Impaired antigen-specific following which the detrimental T-cell-driven proliferation of T-lymphocytes providing immune response evolves and proceeds to insights to study its role for rheumatoid arthritic chronic inflammation. It is possible that etiology. The factors that play important role immunologic defects alter the common in driving T cell function mainly relate to nature mechanism in which a pathogen is cleared by and amount of microbial antigens. Similarly, the host. Examples would include deficiencies regulatory T cell mechanism is essential for involving the complement cascade or antibody preventing autoimmune disorders but it may production. This results in shift towards a also facilitate the establishment of latent cellular immune response with predominated infections via suppression of the host immune activation of either Thl or Th2 of T cells response. An absolute defect in regulatory T subclass. In high synovial inflammation cell function may contribute to the patients with RA showed low CD1a+, CD1b+, development of autoimmune disorders such as and CD1c+ synovial cells count. Such a defect rheumatoid arthritis, type 1 diabetes mellitus, may leads to an insufficient immune response multiple sclerosis and chronic inflammatory against microbial glycolipids, which causes bowel diseases etc., (Kelsen, 2006 ). Similarly inadequate response to infection (Weidler, number of phenotypic and functional T-cell 2004). Neuronal necrosis more severe in defects has been described in RA, including interleukin (IL)-12-defective mice correlated abnormal clonal expansions and suppressed with higher virus titer in the brain. This proliferative responses against microbial indicates type-1 T cell interleukin-12 antigen suggest a defect in T-cell impairment in the control of Semliki Forest differentiation. Defective T cell and its virus (SFV) replication in the CNS lymphokine function resulted with increased pathogenesis (Keogh, 2002). Gamma/delta+ risk of mycobacterial and Salmonella infection T cells in the pathological immune response reported (Barnett, 1992). showed poor proliferation to defective Cell-mediated immunity (Coaccioli, interleukin-2 (IL-2) synthesis, which implicated 2000) and defective mononuclear/macrophage to provide defective helper effect in inducing B response in patients with SLE attributed to cells to secrete immunoglobulins (Gerli et al., increased susceptibility to infection (Passero, 1993). Concomitantly, functionally defective 1981). In addition encapsulated bacterial Fc(IgG)+ T cells’ important role in impaired pathogens like Pneumococcus or immune regulation to SLE patients has also Haemophilus influenzae stimulate microbial been demonstrated (Sakane et al., 1978). clearance through T-cell independent pathway In addition evidence of T-cell documented [Galin and Malech 1990]. differentiation defect in RA could explain some Similarly defect within the particular of the well-characterized immunologic features component of the will result in of the disease (Ponchel et al., 2002). CD4+ an alteration in the way the pathogen activated memory T cells from patients with early immune response. For example, quantitative untreated RA manifest an intrinsic abnormality reduction of K pneumoniae-responsive T cells in their ability to differentiate into specific in Ankylosing Spondolysis (AS) patients cytokine-producing effector cells that might showed defective peripheral T cell defense contribute to the characteristic Th1-dominated against Klebsiella sp. and further it allows chronic autoimmune inflammation in RA bacterial antigens to reach the synovium (Mangelli, 2003; Boyle, 2001). Concomitantly (Hermann et al., 1995). It seems that defect in active RA patients showed abnormal CD28 T cell arm further perpetuate infection which up-regulation suggest modulated CD28 might prove its vulnerability in autoimmune surface levels (Romagnani 1994). Though phenomena, because multiple infection at one such experimental evidences from different time may have deleterious defects in the host. authors could be taken together to suggest Fine specificity of T cell responses to principle defect in determining microbial antigenic epitopes of a particular microbe has antigen through T cell function will leads to importance in providing tolerance. In adjuvant defective consequences which cause arthritic model T cell clones specific for nine deleterious effects in the host. Corresponding amino-acid sequence of Mycobacterium to initial dysregulation or malfunction in T cell tuberculosis antigen provided significant arm may serve undesirable effects later in the

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 tolerance against common microbial antigens. erythematosus (SLE) (Cappione, 2005). Such intrigue would be given more importance Recently Pugh (2006) demonstrated B cells of for studies relate to defective cascading SLE patients with molecular signaling defect, events. which likely to contribute to pathogenesis of the disease and explain the characteristic B cells hyperactivity of B cells in active disease. Person who develops RA may have aberrant On the above, microbial antigen immune response to common microbial connection to defective BCR signaling much antigens or other antigens in the environment. speculate upon their role in autoimmunity. Such response might be caused by intrinsic Autoimmunity-associated B cell defective BCR defects in B cell arm in the immune system. signaling and subsequently regulation of Defective B cells involvement to arthritic microbial lippo-polysaccharides-driven manifestation has been deled widely for their antibody responses has number of involvement in autoimmune manifestation. downstream events in signaling pathways of B Studies on the B cell population and its cells. Hence it may be proposed that defective antibody production in human and animal BCR mediated signals altering intracellular models have suggested involvement of both signal, and thereby changing the strength of intrinsic B cell defect and abnormal regulation signals needed to initiate BCR mediated to common microbe for arthritic manifestation. activation. In addition inherent abnormality of Defects in B cell tolerance play an important B cells and its lymphokines to external signal role in the pathogenesis of systemic such as bacterial lipo-polysaccharides and autoimmune diseases. Recruitment of B cells similar bacterial products has been well depends on antigenic milieu-established documented (Defranco, 1993). The defect can threshold for B cell receptor signaling, which is result from aberrant regulation of antigen modulated by numerous co-receptors, which processing for IgM production; this may be a implicates upon their importance in predisposing factor in systemic autoimmune development of autoimmunity. B cell diseases (Roy, 2005). Mice develop lupus-like responses are mediated by different patterns syndrome to defective autoantibody production of gene expressions, BCR signaling threshold possess immunologic abnormalities suggest B and cellular interactions. Aberrant B cell cell tolerance may be defective against responses are reviewed in the light of these common microbial antigens (Anderson, 1995). principles taking into account the molecular Similarly defective auto-antigen and architectural aspects of immunopathology. signaling through BCR signal may have role in B cell hyper-reactivity may arise from altered generation and maintenance of self-reactivity BCR signaling thresholds in autoimmunity. of B cells in primary immune deficiency (PID). Defects in such stimuli may guide for intrinsic Arthritis most commonly occurs chiefly in response to microbial antigen and defective B humoral PIDs like agammaglobulinemia, cell gene expression. On the above, the common variable immunodeficiency, hyper- interaction between immune cells cellular and IgM syndromes, IgA deficiency, chronic signaling components involvement in B cell granulomatous disease and Wiskott-Aldrich development and maintenance has prime role syndrome etc., Arthritic patients with PID is in understanding RA manifestation. Because usually infectious in nature, the most common modulated expressions of presumed key causative organism is being Mycoplasma, regulatory or signaling components have followed by Staphylococcus, Streptococcus, resulted in subsequent development of and Haemophilus. These bacteria’s can immune dysfunction and autoimmune disease. induce not only synovial infections but also The B cell traverse is tightly regulated aseptic arthritogenic inflammatory responses. development pathway from early progenitors PID syndromes provide insight into the to terminally differentiated plasma cells. Many pathophysiology of bone and joint of these developmental steps are dependent abnormalities associated with immune on signals mediated through receptor-ligand dysfunction (Cuomo, 1995). interactions. Recent results shows that RA Many studies proposed several patients suffer from defective central and infectious agents leads to recognition of self- peripheral B cell tolerance checkpoints may antigens consequently to the disordered favor the development of autoimmunity immune response and dysregulation of (Samuels, 2005; Yurasov, 2005; Currier, production, which initiates and 2000). Using tonsil biopsy study on maintains the disease (Tedder, 1997; Sordet, autoreactive B cells provided evidence for 2005). Patients infected with B19 virus showed defective tolerance checkpoint that appears to elevated IgM antibodies and lack of specificity be specific for human systemic lupus against viral minor capsid species suggested a

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 class switch defect (Bijlsma, 1999). It is also explanation for autoimmune phenomena. suggested that patients with congenital Thus, B cell defective function and defective acquired immunodeficiency may produce BCR signaling on the regulation of bacterial antibodies that fail to react with the viral capsid antigen-driven antibody response accounting protein epitopes. On the above, some for architectural aspect of immunopathology, experimental evidences pertains to disordered which would render deleterious effects in the immune response against common virus host. infection needs to be discussed. Epstein-Barr virus infections of B cells cause the cell to Colony Stimulating Factors (CSFs) and display increased binding sites on the cell Cytokines surface for human Herpesvirus-6, thereby Colony Stimulating Factors (CSF) being as increasing susceptibility to super-infection chemotactic in nature has led RA (Fish, 1989). Lymphocytes from EBV-immune pathogenesis lies in the comprehension of RA patients infected with EBV in culture arthrotopism of antigens and inflammatory produced increased number of cells for joints. Immunological studies have immunoglobulin-secreting cells suggesting learned that host defense against defect in suppressor-T cell function related to disseminated microbes is based on the EBV specificity. Since EBV persists in host B complex interplay between innate and cell- cells, the potential stimulus for immunoglobulin mediated immunity and their CSF with production. This virus persistence along with a cytokine function (Barrett and Sleasman, specific regulatory T-cell defect, may 1990). Large body of clinical experience on contribute to many of the immune the adverse consequences of cytokine abnormalities underlying rheumatoid arthritis administration has accumulated since the last (Tosato, 1981). Lymphocytes and polyclonal B decade. Side effects reported after the cells of RA patients cultured with Epstein-Barr therapeutic use of cytokines has provided virus (EBV) produced less IgM after one week evidence for activation of immune response and increased IgM secretion at the end of may sometimes have deleterious second week and greater IgM after fifth week consequences. Several effects appeared as a suggest that defective B and T cell responses direct consequence of the immune activation to EBV in lymphocytes of RA patients (Irving, induced by cytokines. Cytokine-induced 1985). Considering above studies viral exacerbations of immune dysregulation were infection with disordered immune response growing concern. Interferon-alpha (IFN-alpha) has role in RA like diseases. Hence it may be treatment clearly linked with the exacerbation suggested that immune deficiency might have or the occurrence of several types of contributory role in autoimmune phenomena, autoimmune diseases like thyroiditis, systemic but only with causative organism gives more lupus erythematosus and arthritis. Growth satisfactory explanation. In age related factors and CSF are more specifically linked syndrome effective memory B cell activity is with the development of dermatological more importantly necessary to maintain inflammatory diseases through neutrophils, avoiding cross-reactivity. Re-infection of same monocytes, macrophages or eosinophils old microbial antigens always frequently deled activation. Candida albicans infection with by memory B cells. Memory B cells elicited defective immune response (Vonk et al., 2006) weak primary response to antigen of re- and granulocyte-macrophage colony- infection on transfer to immunodeficient mice stimulating factor-deficient mice failed has been reported (Inman, 2006). In addition response against antigen alpha- maintenance of memory B cell population by galactosylceramide showed intrinsic defect exposure to environmental antigens including and defective immune cell differentiation and viruses, bacteria and other parasites provided development (Bezbradica et al., 2006). intermittent immune stimulation through cross- Concomitantly phenotypical or morphological reactive epitopes. analysis of cells from GM-CSF-supplemented- Furthermore, RA patients’ B cells bone marrow-culture showed quantitative and failed to proliferate against interleukin-2 &10 qualitative alterations of the dentritic cell (DC) supplements, supports the notion that these lineage and increased generation. It has been cells play important role in the pathophysiology proposed that, high number of granulocytes of RA (Reparon-Schuijt et al., 2001). Defective favors inflammatory environment by interfering B cell auto-regulation involvement in the with DC development because unbalanced pathogenesis and chronicity of the disease antigen presenting cell function, which leads to also reported (White, 1986). Taken together T cell autoimmunity (Fuhler, 2004). Likewise the experimental evidences pertain to TNF-deficient cells found less responsive to defective B cell function giving satisfactory infectious agents. Recently Wright (2006)

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 demonstrated in vitro cultured mast cells from predisposes to defective immune response. TNF-deficient mice with reduced expression of Neutrophils are fundamental to the high affinity IgE receptors and reduced inflammatory process, they migrate into number of peritoneal mast cell. inflammatory foci where they manufacture and In addition, IFN-beta-/- mice showed release numerous substances, which if not reduced spleen and bone marrow (BM) controlled may injure the tissues they come in macrophages, defective B cell maturation, contact with. This enhanced activity is decreased CD43-ve bone marrow (BM)- responsible for the degenerative reaction, derived cells, reduced IgM, and CD23 which occurs in rheumatoid arthritis. Recently expression. Likewise circulating IgM, it has been shown that granulocyte–colony- Macrophages and Granulocytes positive cells stimulating factor (G-CSF) and interferon- found decreased in IFN-beta-/- mice. The (IFN- )–activated human neutrophil released decreased number of circulating macrophages remarkable amounts of soluble B-lymphocyte and granulocytes likely to reflect defective stimulator (BLyS) in vitro. Similarly, pro- maturation of primitive bone marrow inflammatory stimuli such as chemotactic hematopoiesis and reduced colony-forming factors, cytokines, immune complexes, and units (Deonarain, 2003), thus providing bacteria-derived lipo-polysaccharides (LPS) insights into importance of CSF in the events trigger and greatly amplify the release of BLyS of primary and secondary immune responses. by inflammatory neutrophils. This B- Concomitantly, qualitative defect in white lymphocyte stimulator (BlyS) released by blood cell count altered white blood cell neutrophils implicated to dysregulated B-cell function and increased susceptibility to homeostasis (Patrizia Scapini 2005). In infection as well. Similarly release of immature addition abnormal synovial fluid neutrophil white blood cells into the circulation caused function to different susceptibility against defect in clear infection and increased various infections in patients with rheumatic propensity to organ failure (Livingston 2003). disorders have been well documented (Wong, Joint inflammation in -/Delta vav mice 2006; Dolganiuc, 2000). characterized by increased number of The association between neutrophils in the inflamed synovium, bone complementary protein C1q and autoimmune marrow, peripheral blood and spleen most diseases such as rheumatoid arthritis and likely due to enhanced responsiveness to G- systemic lupus erythematosus (SLE) are well CSF and IL-6 during arthritis (Kerr, 2004). established. Deficiency in C1q considered Likewise impaired viral clearance in IL-18- strong susceptibility factor for development of deficient mice implicated for RA (Nakanishi, rheumatic diseases. Similarly the observation 2001). Furthermore in GM-CSF exacerbated of the presence of high-affinity autoantibodies collagen induced arthritis (CIA), GM-CSF against C1q antibodies in patients with SLE administration at the antigenic site has been provides strong correlation between C1q and recognized as effective adjuvant for increasing inflammatory process. Recent evidence using cellular and humoral immunity to C1q-deficient mice has showed presence of peptide/protein antigens. Thus, studies glomerulonephritis with immune deposits and corroborate the importance of defect in large number of apoptotic bodies in the immune response against common microbial diseased glomeruli suggesting a defect in the antigens are related to deficient CSF network apoptotic activity by macrophages and or cytokine modulation. From the above dendritic cells (DCs). These data’s are experimental evidences, deficient CSF consistent with the hypothesis that, C1q network, TNF-deficiency induced less effective deficiency may induce a generalized failure to IgE immunoglobulin synthesis and IFN- clear immune complexes. Furthermore, low deficient mice with defective maturation of B serum complement levels found in patients cells are strongly advocate those that principal with autoimmune diseases generally reflect defects upon their role in autoimmunity. increased consumption of complement Those intrinsic defects while dealing microbial proteins as a result of immune complex- antigens may serve potential and favorable mediated inflammation (Ghebrehiwet and environment for infectious agents to facilitate Peerschke, 2004). undesirable effects in the host. Inherited deficiencies in the complement components of the classic Neutrophils cascade carry risk for the development of Polymorphonuclear neutrophils (PMN) play a systemic lupus erythematosus (SLE) and central role in the elimination of most juvenile arthritis. Patients reported to have extracellular pathogenic microorganisms. homozygous C4 deficiency with clinical Impairment of its functions therefore manifestations of autoimmunity. Approximately

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 one-half of the individuals with symptomatic dysregulation of B cell homeostasis, deficient C2 deficiency have autoimmune disease complementary protein activity induced (Hauptmann, 1998). C2 deficiency observed defective clearance of immune complexes by with increased incidence of bacterial apoptotic cells are corroborate the idea that pneumonia, meningitis, and sepsis. Similarly defective neutrophil function has satisfactory deficiency of Cl inhibitor showed uncontrolled explanation for development of autoimmunity. activation of classic pathway components and Because immune-complexes may have consumption of C2 and C4 that leads to potential immunogens and those can induce recurrent episodes of angioedema of the re-stimulation of immune system. viscera, soft tissues, and airway, and high risk Concomitantly complement deficiency with of SLE, Crohn's disease, and Sjogren's increased incidence of bacterial infection syndrome (Brickman, 1986). herewith pursues the importance of defective In addition SLE, systemic vasculitis, complement cascade relation to development and glomerulonephritis reported with C3 of RA like inflammatory diseases. deficiency (Borzy, 1988). Raynaud's phenomena and lupus-like syndromes Matrix metalloproteinases (MMPs) reported with defects in terminal complement In rheumatoid arthritis cartilage damage guess components (Ross and Densen, 1984). protease enzymes connection to erosion at the Cytolysis by terminal complement components site of inflammation. The regulation and is important in host defense against Gram- expression of MMPs considered multi-factorial, negative organisms like Neisseria and brucella and it considered a micro environmental species. Defects in the alternative complement process prevails in the inflammatory region, pathway are more commonly associated with their release being stimulated by exposure to recurrent pyogenic infections, particularly specific activating factors or stimulatory factors infections with Neisseria meningitidis and such as IL-1 and TNF alpha (Cronstin, 1993; Streptococcus pneumoniae. Chronic Arend, 1995; Poole; 1993). Pro-inflammatory granulomatous disease (CGD) is an X-linked cytokines induced matrix metalloproteinase recessive condition characterized with enzymes up regulates mediators such as recurrent infection of catalase-positive adhesion molecules and further reinforces the organism Staphylococcus aureus (Galin and inflammatory activity (Kuo, 2006). Elevated Malech, 1991). In the chronic phase of levels of MMP-9 demonstrated in synovial Chlamydia-induced arthritis the Rac-deficient fluids of rheumatoid arthritis correlated to the mice developed more severe arthritis and severity of the disease. MMP-9 knockout mice demonstrated defective clearance of the inoculated intravenously with Staphylococcus pathogen from the joint (Zhang, 2005). Balb/c aureus displayed significantly higher frequency mice defective with IL-10 gene intravenously and severity of arthritis. This knockout mouse inoculated along with bacteria showed more also proved to harbour increased number of frequent and destructive arthritis with higher bacteria locally in joints and systemically in bacterial load in blood and kidneys (Gjertsson, kidneys and leukocyte deficiency against 2002). In addition, peripheral blood, synovial infection (Feldman, 1996). This indicates that fluid and synovial tissue samples from patients deficiency in MMP-9 increases the degree of with recent Salmonella infection of RA patients joint inflammation due to decreased bacterial study showed positive levels of macrophage clearance. In addition damage to the receptor. This suggest defective host defense respiratory epithelium by viral infection in against gram-negative bacteria (Seta, 2001). MMP7-Knock out mice lead consistent chronic Furthermore the defects in PMN function allograft rejection, suggesting a role for MMPs observed in murine model of autoimmunity in epithelial injury in bronchiolitis obliterans with spontaneous production of TGF-beta syndrome (Conley, 1985). Those data’s possibly play a crucial role in the pathogenesis assume the defective MMP regulations are by infection (Gresham et al., 1991). connected with joint inflammation and bacterial In G-CSF receptor (G-CSFR) deficient clearance. mice with impaired IL-8 activity demonstrated selective defects in PMN activation (Betsuyaku Defective apoptosis et al., 1999). Neutrophils from SLE patients Apoptosis plays an important role in displayed increased DNA damage and autoimmune diseases. Defective apoptosis the demonstrated defective repair of oxidative idea has been introduced to autoimmune like DNA damage (McConnell, 2002). From the degenerative diseases with induction of many above experimental evidences includes LPS- proteases which damage and clear induced B lymphocytes stimulating factors macromolecules of the cartilage region. A from neutrophils and its relation to common feature systemic lupus

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Review Article Biology and Medicine, 1 (3): Rev1, 2009 erythematosus (SLE) is breakdown of responsible for CTL activity against tolerance to self-antigens, a consequence of Mycobacterium tuberculosis super-antigen. which is the production of autoantibodies In addition, increased rate of epithelial reactive with multiple self-proteins. Many cell apoptosis in SS may result from either the evidences are accumulating for modification of imbalance between the down-regulated autoantigens during apoptosis leading to the apoptosis-inhibitor (autocrine) or by the up- development of autoantibodies. Similarly regulated apoptosis-inducer (paracrine or defective apoptosis can cause autoimmunity Fas/FasL) interaction. Defective Fas/FasL- by allowing the survival of autoreactive T and mediated apoptosis of T cells renders arthritis- B cells. Defective apoptosis acts as source of resistant B6 mice susceptible to the immunogen and accelerates abnormal development of chronic erosive arthritis processing of apoptotic cell, which could leads subsequent to mycoplasma infection (Hsu et to auto-antibody production. Defective T cell al., 2001). Eguchi (2001) demonstrated T and apoptotic pathway promotes survival of B cell defective apoptosis with failure in proper potential autoreactive proinflammatory cells. clearance of immune cells and defective Thus failure to eliminate activated cells can down-modulated immune response in mice, result in prolonged effector function and which speculates apoptosis defects, including inappropriate survival of primed autoantibody- defects in Fas, Fas ligand and Fas apoptosis producing B cells (Mulherin, 1996). signaling, may play a role in defective down- Furthermore, it has been suggested that modulation of hyper-immune response in defects in the modulation of programmed cell human autoimmune diseases (Eguchi, 2001). death may lead to autoimmune disease. In addition defective apoptosis has been Altogether, the idea that defects in the reviewed along with promoting autoreactive T apoptotic process could be important for cells and pro-inflammatory cells production explaining autoimmune diseases and makes and failure in clearing activated cells resulted research on the different factors in this in prolonged survival of autoantibody pathway valuable for achieving a better producing B cells. This implicates upon their understanding of the etiopathogenesis of role in RA like immunopathology diseases. autoimmune diseases. Infiltration Especially breakdown of tolerance to self- mononuclear cells lead destruction of antigen consequent with autoantibodies parenchymal tissue showed apoptosis of the reactive with self-antigens has possible acinar and ductal epithelial cells of the salivary explanation for defective apoptosis and lachrymal glands suggested possible involvement to arthritic phenomena. impairment of secretary function in Sjogren Syndrome (SS). Conclusion In the fas-defective MRL-lpr/lpr mice One way or another, the autoimmune staphylococcal enterotoxin super-antigen mechanism has potential and satisfactory systematic administration caused inflammatory explanation for infectious connection. arthritis in the knee joints (Edwards, 1996), Obviously, immunity to common microbial and human endogenous retrovirus HERV-K18 antigen is the pre-requisite for induction of super-antigen level in the JRA patients immune cascading events. Trigger of immune suggesting a possible mechanism for response to denatured fragments of post autoimmunity by super-antigen stimulated infection or to denature self- molecules throw autoreactive T cells (Sicat, 2005). Phagocytic the way for intrigue or undesirable effects in activity of mice estimated by the carbon the host. Obviously defective immune clearance test following injection of response against a common microbial antigen Mycoplasma arthritidis showed significantly might favour the undesirable situation in the depressed phagocytic activity in post-infection host. RA is one in that, hence immune may be related to super-antigen activity with deficiency has contributory role in autoimmune the production of mediator like macrophage phenomena but only with causative organism deactivating factor (Kaklamani 1993). giving satisfactory explanation for etiology. Recently our study related to arthritic model Especially defective B cell function, defective using heat killed Mycobacterium suspended BCR signaling mechanism, dysregulated adjuvant in rats showed invasion of cytotoxic T cytokine function, autoantibodies cross lymphocytes in knee joints region, which reactivity to self-antigens, inappropriate implicated to damage and clearing of cartilage complement cascade and defective apoptosis macromoleules (Subramanian and are few privileged environments needs to be Ramalingam, 2005). On the above it may be understood in-depth. From the above suggested that defective apoptosis may experimental evidences it may be understood that not only infectious connection is the fact

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