Identification of a Novel Non-desmoglein Autoantigen in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The pathogenic role of anti-Dsg antibodies is well-established, while the mechanism of blister formation is only partly defined. We have applied a previously developed method for the efficient immortalization of IgG+ memory B cells to identify novel target antigens in PV. A human monoclonal antibody reactive with a hitherto unreported non-Dsg antigen was isolated. Immunoprecipitation and immunoblotting studies with keratinocyte extracts indicated α-catenin as the putative antigen, then confirmed by immunoblotting on the recombinant protein. Four of ten PV sera reacted with recombinant α-catenin. Although the isolated human monoclonal antibody was per se unable to dissociate keratinocyte monolayers and also to synergize with a pathogenic antibody in vitro, further studies are warranted to assess its possible in vivo contribution in the multifactorial pathogenesis and heterogeneous manifestations of PV disease.

Immune responses to self-antigens in asthma patients: clinical and immunopathological implications.

Asthma leads to chronic airway inflammation that shares pathological features of chronic rejection after lung transplantation. Due to the significant role of autoimmunity in chronic rejection, we hypothesized that immunity to self-antigens may also be present in asthma. The goal was to define immune responses to self-antigens in patients with asthma. Blood and clinical data were collected from 99 asthmatics and 60 controls. Serum was analyzed for antibodies (Abs) to collagen V (ColV) by enzyme-linked immunosorbent assay and correlated with disease severity. Asthmatics' sera were tested in a human protein array to determine immune responses to other self-antigens. Asthmatics had higher concentrations of Abs to ColV (predominantly immunoglobulin G isotype) compared with controls (p < 0.01). These Abs correlated with severe asthma (p < 0.01) and corticosteroid use (p = 0.032). Additionally, Abs to novel self-antigens epidermal group factor receptor (EGFr), activin A type 1 receptor, and α-catenin were detected in asthmatics. We conclude that Abs to self-antigens (ColV, EGFr, activin A type 1 receptor, and α-catenin) are present in the sera of asthmatics, correlating with clinical disease. Epithelial damage from airway inflammation during asthma may result in the exposure of cryptic self-antigens or their determinants, resulting in immune response to self-antigens, which may contribute to the pathogenesis of asthma.

Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes.

Alternatively activated macrophages (AAMs), triggered by interleukin-4 (IL-4) and IL-13, play a modulating role during Th2 cytokine-driven pathologies, but their molecular armament remains poorly characterized. Here, we established E-cadherin (Cdh1) as a selective marker for IL-4/IL-13-exposed mouse and human macrophages, which is STAT6-dependently induced during polarized Th2 responses associated with Taenia crassiceps helminth infections or allergic airway inflammation. The IL-4-dependent, arginase-1/ornithine decarboxylase-mediated production of polyamines is important for maximal Cdh1 induction, unveiling a novel mechanism for IL-4-dependent gene transcription. At the macrophage surface, E-cadherin forms a functional complex with the catenins that accumulates at sites of cell contact. Macrophage-specific deletion of the Cdh1 gene illustrates the implication of E-cadherin in IL-4-driven macrophage fusion and heterotypic interactions with CD103(+) and KLRG1(+) T cells. This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13-exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions.

Autoantigens identified by screening a human heart cDNA library with acute rheumatic fever sera.

Acute rheumatic fever (ARF) is an autoimmune sequela of group A streptococcal infection mostly affecting school-aged children. Recurrent episodes of ARF can result in the development of rheumatic heart disease (RHD). One in 40 indigenous Australians in the Northern Territory is affected by RHD. This disease mostly impacts young people; 45% of those who require heart valve surgery in Australia due to RHD are younger than 25 years old. ARF is characterized by autoimmune attack of the heart; therefore, the presence of the autoantibodies involved could potentially be used to diagnose ARF. To this end, a human heart cDNA library was screened with serum from a patient with ARF, and 12 autoreactive human heart antigens were identified. They include five different IgG heavy chains and a range of tissue-specific cell-signaling proteins, species of which have been implicated in other autoimmune diseases. Preliminary ELISA results show that ARF patients have significantly higher levels of antibodies recognizing the cardiac autoantigens than controls. These antigens are promising candidates for the development of a serological assay for the diagnosis of ARF. The nature of the proteins identified has exciting implications for future research into the pathogenesis of ARF.

Airway modeling and remodeling in the pathogenesis of asthma.

PURPOSE OF REVIEW: Asthma remains a severe health problem since current therapies are directed to suppressing, rather than preventing or reversing, the primary disease process. Clearly, a greater understanding of the pathogenesis of asthma is critical to the development of better therapeutic modalities. In this review, we discuss the recent advancements in research targeting the role of airway remodeling in asthma. RECENT FINDINGS: Epithelial fragility and abnormalities are being recognized as important facets of asthma, as are other features of remodeling such as angiogenesis, goblet cell hyperplasia and thickened lamina reticularis. Significantly, these anomalies occur early in disease pathogenesis. However, their impact on disease severity remains unclear. SUMMARY: Although an altered immune response is undoubtedly important to the pathogenesis of asthma, there is increasing evidence that the tissue-specific manifestations occur independently of inflammation and significantly impact on disease development and severity.