7 research outputs found
The Protease Inhibitor Alpha-2-Macroglobuline-Like-1 Is the p170 Antigen Recognized by Paraneoplastic Pemphigus Autoantibodies in Human
Paraneoplastic pemphigus (PNP) is a devastating autoimmune blistering disease, involving mucocutaneous and internal organs, and associated with underlying neoplasms. PNP is characterized by the production of autoantibodies targeting proteins of the plakin and cadherin families involved in maintenance of cell architecture and tissue cohesion. Nevertheless, the identity of an antigen of Mr 170,000 (p170), thought to be critical in PNP pathogenesis, has remained unknown
Th2 cells mediate IL-4-dependent local tissue inflammation
We investigated whether polyclonal murine Th1 and Th2 cells obtained after short term culture in vitro were capable of mediating tissue inflammation in vivo. Th cells were pulsed with mAb to the TCR/CD3 complex and injected into the footpads or ears of naive syngeneic recipient mice. Th1 induced delayed swelling that peaked at 24 to 48 h and lasted > or = 5 days. Th2-induced swelling peaked at 6 h and lasted < or = 48 h. Similar responses were also observed in athymic nude mice. Lesions with both Th1 and Th2 cells contained a predominant neutrophilic infiltrate at 6 h, and mainly mononuclear cells at 48 h. The inflammatory response with Th2 was blocked by cyclosporin A, by mAb to IL-4 or by soluble rIL-4R. The requirement for IL-4 was early and transient. Four alloreactive short term Th2 clones induced swelling in allogeneic recipients. mAb- and IL-4-dependent swelling responses were also observed with two long term Th2 clones. Our results demonstrate that Th2 cells mediate IL-4-dependent tissue inflammation, and strengthen the concept that Th2 cells play an important role in some T cell-dependent immune reactions and, possibly, in allergic disorders such as atopic dermatitis and allergic asthma
IgG autoantibodies from bullous pemphigoid (BP) patients bind antigenic sites on both the extracellular and the intracellular domains of the BP antigen 180
Bullous pemphigoid (BP) and gestational pemphigoid (PG) are subepidermal blistering disorders associated with autoantibodies directed against two components of hemidesmosomes: the BP antigen 180 (BP180) and the BP antigen 230 (BP230). Autoantibodies against the extracellular domain (ECD) of BP180 are thought to play an initiatory role in subepidermal blister formation. To characterize the targeted antigenic sites on BP180, we have assessed the reactivity of sera from BP and PG patients against eukaryotic recombinant proteins encompassing various portions of the ECD and the intracellular domain (ICD) of BP180. Twenty-two of 22 (100%) BP sera that immunoblotted BP180 in keratinocyte extracts, bound a mutant form consisting of the entire ECD of BP180, whereas only three of these 22 sera (14%) reacted against the ECD of BP180 lacking the NC16A membrane proximal region. Thirteen out of the 22 (59%) BP sera recognized the ICD of BP180. Circulating IgG from a representative BP patient that was affinity purified against the ECD of BP180 did not bind the ICD when reblotted, indicating that there was no antigenic cross-reactivity between the ECD and the ICD of BP180. Reactivity against the ICD of BP180 was further ascertained by immunofluorescence microscopy studies showing that nine of the 22 (41%) BP sera stained COS-7 cells expressing the ICD of BP180. Using deletion mutants of the ICD of BP180, the majority of the sera was found to recognize the central region of the ICD of BP180. Specifically, an immunodominant region was localized to an 87-amino acid segment located towards the NH2-terminus of BP180. In contrast to BP sera, five of six (83%) PG sera contained IgG that recognized exclusively the NC16A region, whereas none bound to the ICD of BP180. Together, the results indicate that in BP, autoantibody reactivity to BP180 is not exclusively restricted to the NC16A region, but that additional antigenic determinants exist on the ICD of BP180. The observed heterogeneous immune response against BP180 might reflect intramolecular epitope spreading. Because the ICD ofBP180 harbors functionally important regions, it is possible that autoantibodies against the ICD of BP180 have pathogenic significance for the progression of the disease