The environmental factors that contribute to the development of autoimmune diseases are largely unknown. Endemic pemphigus foliaceus in humans, known as Fogo Selvagem (FS) in Brazil, is mediated by pathogenic IgG4 autoantibodies against desmoglein1 (Dsg1). Clusters of FS overlap with those of leishmaniasis, a disease transmitted by sand fly (Lutzomyia longipalpis) bites. In this study we show that salivary antigens from the sand fly, and specifically the LJM11 salivary protein, are recognized by FS antibodies. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11. Mice immunized with LJM11 generate anti-Dsg1 antibodies. Thus, insect bites may deliver salivary antigens that initiate a cross-reactive IgG4 antibody response in genetically susceptible individuals and lead to subsequent FS. Our findings establish a clear relationship between an environmental, non-infectious antigen and the development of potentially pathogenic autoantibodies in an autoimmune disease.

StlmmaryMice homozygous for the Ipr gene have a defect inJ~s (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CDS-(double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-1pr/Ipr (B6/Ipr) mice that were deficient for the 32-microglobulin gene (32m-lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only "y/~+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V3 expression of the remaining DN T cells in 32m-Ipr mice showed a shift to a CD4-1ike repertoire from a CDS-like repertoire in control B6/Ipr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I.We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the fl2m-lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing 3'/~ are also affected by the lpr defect and become minor components of the aberrant DN population.

It is well established that autoantibodies against desmoglein 3 and desmoglein 1 are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form, Fogo Selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine if FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E-cadherin. Testing a large number of FS and endemic control sera by ELISA we find a consistent and specific autoantibody response against desmoglein 1 and other keratinocyte cadherins in these individuals, which is quite different from US controls. Overall, the highest correlations among the autoantibody responses tested are in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross reactive, keratinocyte cadherins are recognized by FS patients and endemic controls.

We have shown that although the IgG response in fogo selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limão Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

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BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (a novel coronavirus), which was first identified amid an outbreak of respiratory illness cases in Wuhan, China and declared a global health emergency, is currently considered an additional challenge in the management of patients with breast cancer (BC). Cancer patients are more vulnerable to becoming infected with severe acute respiratory syndrome coronavirus 2 and are more likely to suffer additional complications that can increase mortality. Identifying those BC patients who require more urgent therapy than others in the current situation is essential. These recommendations are based on and have been adapted from those similarly published by international scientific societies for BC management. They are divided mainly by clinical stage (early, advanced), subtype [luminal, human epidermal growth factor receptor 2 (HER2), triple-negative], or type of medical treatment and setting (neoadjuvant, adjuvant, metastatic). Recommendations for HER2 and triple-negative subtypes are similar, whereas in luminal subtype there are various options of management. The objective is to adapt guidelines to local context through relevant decision-makers, avoiding duplication of efforts and optimizing use or resources. We hope that these recommendations will help medical oncologists provide the best quality care to BC patients during the COVID-19 pandemic with information tailored to our healthcare system. AIM To establish and adapt recommendations from those published by international scientific societies for BC management. METHODS The Peruvian Society of Medical Oncology developed a consensus and propose here a manuscript with recommendations for oncological medical treatment of BC during the COVID-19 pandemic. The Peruvian Society of Medical Oncology invited a panel of experts and opinion leaders on BC working in major health care systems around Peru. Panel experts selected three international clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, Spanish Foundation Research Group in Breast Cancer), considering that these are more representative in COVID-19 management. Also, the panel agreed to include at least one European and American clinical practice guideline. RESULTS Recommendations about BC management during the COVID-19 pandemic were divided mainly by clinical stage (early, advanced), subtype (luminal, HER2, triple-negative), or type of medical treatment and setting (neoadjuvant, adjuvant, metastatic). Recommendations for HER2 and triple-negative subtypes were similar between clinical practice guidelines, whereas in luminal subtype there were various options of management. One hundred twelve recommendations were reviewed, adapted, and voted. A consensus was made in order to provide best decisions of management, avoid duplication of efforts, and optimi...

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