Involvement of Soluble CD95 in Churg-Strauss Syndrome

Abstract

Deficiency of CD95 (Apo-1/Fas)-mediated apoptosis has recently been found in some autoimmune lymphoproliferative disorders due to inherited mutations of the CD95 gene. In this study , impairment of CD95 ligand-mediated killing of lymphocytes and eosinophils in Churg-Strauss Syndrome (CSS) , which was a result of variation of CD95 receptor isoform expression , is demonstrated. Compared to those from healthy individuals , peripheral blood lymphocytes from eight CSS patients exhibit a switch from the membrane-bound CD95 receptor expression to its soluble splice variant , which protects from CD95L-mediated apoptosis. In five out of seven CSS patients recurrent oligoclonal T cell expansions were found, all using a V␤-gene from the V␤21 family associated with similar CDR3 motifs , indicating the predominance of T cell clones of a similar specificity in the CSS patients. In two of them , the effect of immunosuppressive therapy was studied. In both cases aberrant overexpression of the soluble CD95 receptor isoform and deviations from normal TCR V␤-gene usage normalized in parallel with the clinical improvement. Furthermore , soluble CD95 was identified as a survival factor for eosinophils rescuing eosinophils from apoptosis in the absence of growth factors in vitro. Churg-Strauss Syndrome (CSS) was for the first time described by Lotte Strauss and Jacob Churg in 1951 in The American Journal of Pathology, 1 defining a new entity with systemic vasculitis, blood and tissue eosinophilia, and a long-term history of asthma. Systemic vasculitis in this rare syndrome mainly affects the lower respiratory tract, kidneys, skin, and nervous system. 2 The gastrointestinal tract is involved in about 35% of the CSS cases. 2 Infiltrating eosinophils are frequently found in granulomatous lesions 3 and the fraction of eosinophils in the peripheral blood correlates with the course of the disease, 3,4 suggestive of a role of eosinophils in the pathogenesis of CSS. 5 On the other hand, T cells were frequently implicated in autoreactivity and inflammatory lesions. 6 However, a potential role of T lymphocytes in CSS and the molecular mechanisms underlying this disease have not yet been studied.One tool to analyze T cell populations in clinical samples at the molecular level is the Immunoscope technique. 5 This approach is based on the hypothesis that the expression of unique, rearranged T cell receptor (TCR) genes reflects the specificity of a given T cell. 7 Each TCR-␤ chain consists of a variable (V), diversity (D), joining (J), and a constant region, the first three determining the antigen specificity in their VDJ-junction, including complementarity-determining region III (CDR3). During T cell differentiation, unique variable region genes are created by recombination of V, D and J segments for the TCR-␤ locus. More than 70 V␤ gene segments have been characterized and are classified into 24 gene families 8 ( Figure 1A).In T cells the CD95/CD95 ligand system is a major pathway of apoptotic cell death and thus essential for prevention of lymp...

HLA–DRB4 as a genetic risk factor for Churg‐Strauss syndrome

“…The finding that CSS patients have a restricted HLA repertoire supports the hypothesis that only selected antigenic determinants may be involved in CSS, and simultaneously highlights the pathogenetic role of T cells. In accordance with this view, clonal T cell expansion has been demonstrated in CSS patients, and, because the T cell clones had similarly specific T cell receptors, they could recognize only a limited number of antigens (34). This finding, together with the present results, supports the notion that CSS is an antigen-driven disease.…”

Anti-Neutrophil Cytoplasmic Antibody Pathogenesis in Small-Vessel Vasculitis

“…15,48 Of these, interleukin-5 (which induces eosinophil production, activation, and surveillance) seems to play a critical role. 13 Other impaired apoptosis-related molecules (eg, soluble CD95, 49 tumor necrosis factor-related apoptosisinducing ligand receptor 3, 50 and discoidin domain receptor 51 ) may contribute to the delayed eosinophil clearance seen in CSS. Infiltrating eosinophils release cytotoxic enzymes (eg, major basic protein, 52 eosinophil peroxidase, 53 and eosinophilic cationic protein 54 ) and, ultimately, cause tissue injury.…”

“…In the article by Kain et al, 25 although neither epitope was homologous to MPO or PR3, the P 41-49 epitope was 100% homologous to amino acids 72 to 80 of the mature form of FimH, an adhesin located at the tip of type 1 fimbriae that is essential for the attachment of Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis to host epithelia. Reciprocal inhibition experiments showed that autoantibodies that recognized human LAMP-2, specifically its P [41][42][43][44][45][46][47][48][49] epitope, cross-reacted with FimH. Furthermore, rats immunized with recombinant FimH fusion protein developed antibodies to FimH that cross-reacted with human LAMP-2.…”

“…In addition, autoantibodies from these patients bound the region of human LAMP-2 that contained the cross-reactive P [41][42][43][44][45][46][47][48][49] epitope.…”

SLAM Family Receptors and Autoimmunity

“…These variations in splice isoform expression are likely to have functional consequences and have also been implicated as candidates for other autoimmune susceptibility loci (Evsyukova et al, 2010;Gillett et al, 2009;Muschen et al, 1999;Ueda et al, 2003). One of the strongest candidates of the SLAMF linked to lupus susceptibly in mice is Ly108 (CD352, SLAMF6).…”