Immunological Mechanisms

Immunological mechanisms are considered to play a major role in the pathogenesis of ABD36 (Fig. 4). They include the involvement of heat shock proteins, alterations of the neutrophils and macrophage activity, expression of numerous cytokines and chemokines, and autoimmune mechanisms.

4.1 Heat shock proteins

Heat shock proteins (HSP) are molecules that are synthesised in response to various kinds of stress in all eukaryotic cells37. They also share antigenic epitopes with several bacterial micro-organisms which have been implicated in the pathogenesis of ABD, such as HSV, Streptococcus species and Mycobacteria. T cell epitope mapping has identified four peptides derived from the sequence of a 65 kDa bacterial HSP which stimulate proliferation of y5+TCR lymphocytes of patients with abd38-40. These peptides show significant homology with the corresponding peptides derived from the human 60 kDa mitochondrial HSP41. In the cerebrospinal fluid of patients who had parenchymal neurological involvement an increased level of anti-HSP antibodies could be found42. On the other hand, immunoglobulin A isotype of antibodies specific for mycobacterial tuberculosis HSP-65 could cross react with certain serotypes of Streptococcus sanguis43. In general, cross reactions between microbial and human 65-kDa HSP possibly link infection with autoimmunity.

bacterial stress up regulates


stimulate yS and ap TCR* cells, B cells and neutrophils to generate

CD4+ effector CD8+ suppressor neutrophils B cells cells cells I i

TH2 cytokines antibodies chemokines

Figure 4. The suggested immunopathogenesis of Adamantiades-Behpet's disease (from Lehner, T,, 1999, Ann. Med. Interne (Paris) 150: 4B3-48736)

The hypothesis that a 65-kDa HSP antigen determinant is involved in the aetiology and pathogenesis of BD is supported by (a) raised serum IgA antibodies to mycobacterial 65-kDa HSP40, (b) autoantibodies to oral epithelial antigens43, (c) cross reactivity between a number of monoclonal antibodies to mycobacterial HSP and Streptococcus sanguis42, (d) cross-reactivity between polyclonal antibodies to mycobacterial HSP and oral epithelial antigens, and (e) significant increase of both circulating and inflammatory site infiltrating T cells during the active phase of the disease. The up-regulation of T cells observed in ABD patients suggests that the aetiological agent(s) may include 65-kDa HSP peptides shared between common bacteria and human tissues, superantigens such as bacterial toxins, or viruses39'44. Interestingly, the MICA protein of the MHC region is recognised by T-cells with a variable VdlyS region in their T-cell receptor and antigens presented to T-cells are assisted by the MICA


4.2 Neutrophil function

Neutrophil chemotaxis and phagocytosis are increased in cutaneous lesions of ABD patients46-48. Leukocyte adhesion molecules (L-Selectin, MAC-1 and CD44) are expressed on peripheral leucocytes and may participate in the sequential cascades of leucocyte chemotaxis and adhesion. Endothelial adhesion properties are enhanced due to the increased expression of CD 11 a/CD 18 in neutrophil surfaces and ICAM-1 in the endothelium. A higher level of superoxide production in the neutrophils of patients with ABD seems to be related to the presence of HLA-B5148. In conclusion, the enhanced superoxide and excessive production of lysosomal enzymes and enhanced chemotaxis of neutrophils from patients with ABD indicate that the neutrophils are overactive, which leads to tissue injury49'50.

4.3 Monocyte function

The activation of monocytes may explain the production of proinflammatory cytokines responsible for the chronicity of inflammation51. Spontaneous overproduction of TNF-a, IL-6, and IL-8 by patients' monocytes is apparently related to the disease activity. Patients' serum was shown to be able to inhibit the anti-inflammatory molecule AMAC-1 expression on healthy monocytes induced IL-4 and dexamethasone24.

4.4 Cytokine and chemokine mediators

Various pro-inflammatory cytokines such as IL-1, IL-8 and TNF-a are elevated in the sera of ABD patients. Especially, IL-8 seems to play an important role, can be also released by endothelial cells, and is a sensitive marker of disease activity52,53. Cytokine release may be dependent on the involved organ. Elevated levels of IL-6 in the cerebrospinal fluid was found in patients with neurological involvement54, whereas patients with CNS

involvement and oral aphthous ulcers exhibit elevated serum levels of IL-8 . Patients with ocular involvement show increased IL-2-producing cells55. In addition the correlation of TNF receptor-75 levels with disease activity indicates that TNF receptor-75 may serve as a biological marker of disease activity56. The elevation of plasma IL-12 was also shown and the correlation of IL-12 plasma levels with disease activity may suggest a

pathogenetic role of a Thl-type immune response in active disease .

4.5 Autoimmune mechanisms

Autoimmune mechanisms are involved in the pathogenesis of ABD. A number of immunological abnormalities have been identified and circulating immune complexes are compatible with the development of clinical features. The major microscopic finding at most sites of active ABD is an immunemediated occlusive vasculitis50,58. At the cellular level, CD4-T cells were found in the perivascular inflammatory exudate and Thl-cells respond to various stimuli to produce IL-2, IFN-y, and TNF-a46. In addition, patients' lymphocytes express CD29 molecules and bind to endothelial cells in active disease46,59. Cytokines induce B cell proliferation. On the other hand, IL-12

is generated by stimulation of CD4-T cells with the HSP peptide 336-351, and can also be secreted by neutrophils in ABD41. In addition, IL-8 levels are higher in patients with active disease; this cytokine has a potent effect on the

inflammatory response52. Natural killer (NK) cells are increased in peripheral blood in patients with active disease, but their activity was found to be relatively low at the intervals60'61. Decreased NK cell activity may be correlated with increased levels of prostaglandin whereas prostaglandin E2 depresses NK cells activity61,62. Circulating immune complexes together with enhanced neutrophil migration may be involved in the pathogenesis of systemic and mucocutaneous effects of ABD46,2,61

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