Commentary 3

Abstract

Compared with other ‘model’ disorders of organ-specific autoimmunity, such as multiple sclerosis, myasthenia gravis or insulin-dependent diabetes mellitus, the pathogenesis of pemphigus is by far unravelled to the greatest extent (1,2). However, the ambitious endeavour to provide a pathogenetic concept that fits for all the clinical variations of pemphigus demonstrates that, apart from the definition of common major autoantigens, the relative contribution of additional factors may vary interindividually. Several brilliant achievements of the past years have helped to dissect crucial events in the effector phase of the immune pathogenesis of pemphigus, even though several aspects in the aetiology and molecular effects leading to autoimmune loss of epidermal adhesion are not yet fully understood. Immunogenetically, there is a clear-cut association of pemphigus with distinct human leukocyte antigen (HLA) class II alleles that have been shown to be critical for T-cell recognition of autoantigenic peptides of desmoglein (Dsg)3 and Dsg1, an initial event required for T-cell-dependent induction and perpetuation of autoantibody production (2–4). The relevance of this concept is supported by the finding that healthy carriers of pemphigus-associated HLA class II alleles have also autoreactive T cells of identical epitope specificity and similar frequency as patients with pemphigus (4–7). We have shown that Dsg3-specific, T-cell-driven peripheral tolerance is at least one mechanism which regulates the clinical outcome of pemphigus by preventing the activation of Dsg3-specific, autoaggressive B cells (7–9). Several human studies in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) (including the endemic variant, fogo selvagem) have shown that, in general, immunoglobulin G (IgG) autoantibody titres against Dsg3 and Dsg1 relate to the clinical activity and phenotype of PV and PF, respectively (10,11), and that their therapeutic removal is of clinical benefit in PV (12,13). Even though there is a proof that the overall picture of the Dsg compensation theory is valid (11), there are several evidences that autoantibody specificities (i.e. Dsg1 vs Dsg3 reactivity) and titres do not always relate to the clinical phenotype and activity of pemphigus (14,15). With regard to intramolecular epitope spreading, there is strong evidence that polyclonal Dsg-specific IgG autoantibodies in the patients’ sera recognize both pathogenic and non-pathogenic epitopes located in the ectodomains of Dsg3 and Dsg1 (16). Experimental in vitro and in vivo data demonstrate that IgG against the NH2-terminal domain of Dsg3 is pathogenic, while IgG against other epitopes requires the presence of autoantibodies targeting additional epitopes resulting in a pathogenic synergism of ‘semipathogenic’ autoantibodies (17–19). This contention is also supported by serological analyses in PV patients showing (i) that IgG against the NH2-terminal aa1–161 relates to disease activity (20) and (i) that the presence of several domain-specific IgG autoantibodies against the Dsg3 ectodomain relates to disease activity in PV (21). In fogo selvagem, the endemic variant of PF, pathogenic IgG autoantibodies against the putative autoantigen, Dsg1, target its NH2-terminus, while patients’ relatives or individuals who develop disease later on have autoantibodies that target ‘non-pathogenic’ regions in the COOH-terminus of the Dsg1 ectodomain (22). Current evidence favours the concept that Dsg1 and Dsg3 are the principal autoantigens in most clinical variants of pemphigus, even though the relative contribution of additional desmosomal (i.e. desmocollins, plakins) and non-desmosomal autoantigens (pemphaxin, α9-acetylcholine receptor) remains a matter of debate (23,24). The critical role of Dsg3 in epidermal adhesion of mucosal and stratified squamous epithelia has been clearly shown in a Dsg3-deficient animal (25). However, we would like to challenge the concept that Dsg-specific autoantibodies alone are the principal effectors in pemphigus because patients on treatment with the anti-CD20 monoclonal antibody, rituximab, frequently show a clinical response despite the persistence of high autoantibody titres (26). Our group has observed in rituximab-treated PV patients that, upon depletion of B cells, the frequencies of autoreactive T helper 1 and 2 cells were immediately reduced to background levels (27). This was not the case with T helper cells responsive to an unrelated antigen, suggesting that rituximab acted specifically on autoreactive T cells which may also be critically involved in the effector phase of PV, apart from their helper function to autoaggressive B cells (28,29). Along this line, therapeutic blockade with infliximab, a monoclonal antibody against the proinflammatory cytokine, tumor necrosis factor-α, which is mainly produced by effector T cells, leads to an immediate amelioration of PV, despite the persistence of tissue-bound and circulating IgG autoantibodies (30). While this may not suffice to demote Dsg-specific autoantibodies to the inferior role of ‘witnesses of disease’, it clearly questions whether these autoantibodies alone are the principal effectors of PV immunopathogenesis.