Cd And Autoimmunity

Although the pathogenic mechanism of CD is not yet fully elucidated, there is no doubt about the involvement of immune factors in the development of the disease. Many features present in CD fulfil the criteria generally accepted to define autoimmune disease and suggest that CD belongs to this group of diseases [1,11]:

(1) HLA linkage: For the majority of patients, a particular HLA-DQ heterodimer, encoded by the DQA1 0501 and DQB1 0201 alleles on chromosome 6, confers the primary susceptibility to CD [1, 12].

(2) Associated autoimmune diseases: It has been reported that insulin-dependent diabetes mellitus (IDDM) occurs in 1-10% of adult coeliac patients and the prevalence of CD in patients with IDDM has been 2-7%. Similarly, 2-4% of coeliacs suffer from autoimmune thyroid disease and serological screening for CD in patients with autoimmune thyroid disease gives a coeliac prevalence of approximately 4%. The association between Sjogren's syndrome and CD was recently shown: 3-5% of adult coeliac patients had Sjdgren's syndrome and 14% of patients with Sjogren's syndrome had CD [1,13].

(3) Intestinal lymphomononuclear infiltration: lymphocytic infiltration of the intestinal lamina propria and increased numbers of intraepithelial lymphocytes are important diagnostic features of the disease. Intraepithelial cells are mainly CD8+ T lymphocytes with substantially increased proportion of y/8 TCR bearing cells. Plasma cells producing immunoglobulins of all isotypes (mainly IgA) and activated CD4+ T lymphocytes are increased in lamina propria [1],

(4) Presence of specific autoantibodies : Characteristically increased levels of IgA and IgG antigliadin antibodies in sera of coeliac patients are accompanied by high levels of specific autoantibodies reacting with components of the extracellular matrix. Antireticulin, antiendomysium and antijejunal antibodies of IgA isotype were found to have a high degree of specificity and sensitivity for CD [14], Antiendomysial autoantibodies occurring in 90-100% of CD patients are used, therefore, for serological screening of CD [15]. We found that autoantibodies directed to enterocytes occur in most sera of coeliac patients and that both monoclonal and affinity purified antibody directed to gliadin from patients' sera exert reactivity to intestinal epithelial cells [16-18], Furthermore, the occurrence of various autoantibodies characteristic for other autoimmune diseases were found in 5-20% of the sera of CD patients [11],

(5) Existence of defined autoantigens: Two autoanti-genic molecules were recently defined as targets for autoantibodies in CD; the autoantigen of en-domysium was determined as tissue transglutaminase [12, 19, 20], and one of enterocyte autoantigens sharing similar epitopes with a-gliadin was defined as calreticulin [21-23], Tissue transglutaminase is expressed in many tissues and the enzyme is present intracellularly and extracellu-larly. The calcium-dependent enzymatic activity of transglutaminase catalyses deamidation or cross-linking of protein bound glutamine residues. It is suppose that transglutaminase potentiates-binding of gliadin peptides to HLA DR2 on antigen presenting cells and gliadin specific T-helper cells then promote specific antibody response by B cells. Transglutaminase is necessary for activation of transforming growth-factor-/? (TGF/J) and participates in differentiation intestinal epithelium. In the extracellular environment transglutaminase is involved in extracellular matrix assembly and cell adhesion. However, how the external agent, gliadin, leads to generation of IgA autoantibody formation against transglutaminase is still open to speculation [12, 19]. The second defined autoantigen, calreticulin, is a multifunctional high-capacity calcium-binding protein and molecular chaperon which is distributed in a wide variety of cells. It has been found in different locations including the lumen of the endoplasmic reticulum, the cell surface, perinuclear areas, or cy-tosolic granules and is expression seems to vary between cell types. Recent studies showed that this protein interacts with «-subunit of integrins, the steroid/nuclear hormone receptor family, vitamin D receptor, the B-fi chain of fibrinogen, oligoman-nosides of laminin and the polypeptide of Ro/SS-A ribonucleoprotein. There is also evidence to suggest the role of calreticulin in immune processes. The synthesis of calreticulin is stress induced. It has also been reported that calreticulin may be released from the lytic granules of cytolytic lymphocytes after stimulation of the T-cell receptor complex. Similarly as in the case of tissue transglutaminase the role of calreticulin in pathogenic mechanism of CD remain to be elucidated [22].

(6) Response to corticosteroids and immunosuppressive treatment. Severe forms of CD are successfully treated by corticosteroids or immunosuppressive drugs [24-26],

(7) CD is more common in females than in males, similar to other autoimmune diseases [1],

(8) Transfer of mucosal damage by intraepithelial lymphocytes: animal model of CD has been recently introduced in our laboratory by long-term gliadin feeding of rats provided that it starts from birth. Intestinal intraepithelial lymphocytes from rats suffering from gluten induced enteropathy transferred to jejunal loops of inbred recipients caused changes in recipients gut mucosa and were shown to be responsible for mucosa damaging effects [27],

(9) Transfer of the disease by lymphocytes during bonemarrow transplantation: Recently, the transfer of human bonemarrow cell suspension containing T lymphocytes from donor with CD was performed and resulted in CD development in the recipient [28].

(10) Stimulation of natural killer cell activity by gliadin in patients with coeliac disease: Spontaneous cell cytotoxicity, the lysis of susceptible targets by unprimed lymphocytes, is considered to be an important first line of host defense against tumors and infected cells. In peripheral blood, spontaneous cell cytotoxicity is accomplished by NK cells. We did not find significant differences between NK-cell activity of peripheral blood mononuclear cell from healthy donors and patients with CD. However, a 1-day incubation of peripheral blood lymphocytes with gliadin induced cytotoxic cell activity against the natural killer resistant target cells, such as the epithelial HT29 cells and the lymphoblastoid RAJI cell lines suggesting that the activation of peripheral NK cells by gliadin can occur [29].

herpetiformis and the other with CD imply that environmental factors are responsible for the development of the rash in dermatitis herpetiformis. The presence of antigliadin and antiendomysial autoantibodies in sera of patients suggests a common pathogenetic mechanism, but the nature of the autoantigen and its role in the blister formation remains to be elucidated [31].

As with CD, an increased incidence of malignant disease (lymphoma) has been reported in patients with dermatitis herpetiformis. A gluten-free diet appears to protect patients from this complication [32, 33]. The results of these studies give further support for advising patients to adhere to a strict gluten-free diet for life.

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