The role of natural killer cells in autoimmune blistering diseases.

The major focus of this paper is to describe and evaluate current information on the role of natural killer cells (NK cells) in the pathogenesis of blistering diseases. Until now, only pemphigus vulgaris (PV) has been studied. One co-culture study demonstrated that CD4+ T cells from the peripheral blood or perilesional skin of patients with active disease proliferate and secrete cytokines in the presence of major histocompatibility class II-expressing NK cells loaded with antigenic desmoglein self-peptides. Another study showed that NK cells can contribute to a T helper type 2-biased immune response through impaired interleukins (IL)-12 signaling and upregulation of IL, IL-10 and IL-5. Although significant data on other blistering diseases are unavailable at present, some studies implicate NK cells in disease progression. For instance, information on the role of NK cells in psoriasis and their production of tumor necrosis factor-α (TNF-α) will be provided since several TNF-α-inhibitors are used in its treatment. Studies on alopecia areata are also included in this paper because NK cells seem to play a key role in its pathogenesis. This review highlights the potential importance of NK cells and NKT cells as members of the large repertoire of cells and soluble mediators that play a critical role in pathogenesis of blistering diseases and other autoimmune diseases involving the skin. Therefore, the authors advocate a greater focus and interest on the study of the interaction of NK cells and the skin.

Role of MHC Class II genes in the pathogenesis of pemphigoid.

Pemphigoid (Pg) is an autoimmune subepidermal blistering disease that affects the elderly population. The phenotype can be Bullous Pemphigoid (BP), which primarily involves the skin, or Mucous Membrane Pemphigoid (MMP), which primarily involves mucus membranes. Ocular Cicatricial Pemphigoid (OCP) and Oral Pemphigoid (OP) are subsets of MMP. The known antigens in BP are Bullous Pemphigoid Antigen 1 (BPAG1, also known as BP230), Bullous Pemphigoid Antigen 2 (BPAG2, also known as BP180), and subunits of human integrins α6 and ß4. The Human Leukocyte Antigen (HLA) allele HLA-DQß1*0301 has been reported to be associated with enhanced susceptibility to all of these subsets. Sera of patients with the four subsets are characterized by the presence of anti-Basement Membrane Zone (anti-BMZ) antibodies. In this manuscript, we present a model in which relevant portions of the four different antigens involved in pemphigoid have potential sites that could be presented by an antigen presenting cell (APC) in conjunction with DQß1*0301 to a T cell receptor to initiate the process that results in anti-BMZ antibody production. Thus, this model provides a hypothetical computer-based mechanism to explain how a single HLA allele can be associated with the production of antibodies to four different antigens that result in four different subsets of a disease with four different clinical profiles and prognoses.

Relationship between target antigens and major histocompatibility complex (MHC) class II genes in producing two pathogenic antibodies simultaneously.

In this report,we present 15 patients with histological and immunopathologically proven pemphigus vulgaris (PV). After a mean of 80 months since the onset of disease, when evaluated serologically, they had antibodies typical of PV and pemphigoid (Pg). Similarly, 18 patients with bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) were diagnosed on the basis of histology and immunopathology.After a mean of 60 months since the onset of disease, when their sera were evaluated they were found to have Pg and PV autoantibodies. In both groups of patients the diseases were characterized by a chronic course, which included several relapses and recurrences and were non-responsive to conventional therapy. The major histocompatibility complex class II (MHC II) genes were studied in both groups of patients and phenotypes associated typically with them were observed. Hence, in 33 patients, two different pathogenic autoantibodies were detected simultaneously. The authors provide a computer model to show that each MHC II gene has relevant epitopes that recognize the antigens associated with both diseases. Using the databases in these computer models, the authors present the hypothesis that these two autoantibodies are produced simultaneously due to the phenomena of epitope spreading.