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Pemphigus foliaceus (PF) is an autoimmune skin blistering disease characterized by antidesmoglein-1 IgG production, with an endemic form (EPF) in Brazil. Genetic and epigenetic factors have been associated with EPF, but its etiology is still not fully understood. To evaluate the genetic association of histone (de)acetylation-related genes with EPF susceptibility, we evaluated 785 polymorphisms from 144 genes, for 227 EPF patients and 194 controls. Carriers of HDAC4_rs4852054*A were more susceptible (OR = 1.79, p = 0.0038), whereas those with GSE1_rs13339618*A (OR = 0.57, p = 0.0011) and homozygotes for PHF21A_rs4756055*A (OR = 0.39, p = 0.0006) were less susceptible to EPF. These variants were not associated with sporadic PF (SPF) in German samples of 75 SPF patients and 150 controls, possibly reflecting differences in SPF and EPF pathophysiology. We further evaluated the expression of histone (de)acetylation-related genes in CD4+ T lymphocytes, using RNAseq. In these cells, we found a higher expression of KAT2B, PHF20, and ZEB2 and lower expression of KAT14 and JAD1 in patients with active EPF without treatment compared to controls from endemic regions. The encoded proteins cause epigenetic modifications related to immune cell differentiation and cell death, possibly affecting the immune response in patients with PF.

Pemphigus is a chronic autoimmune skin blistering disease, characterized by acantholysis and by the production of autoantibodies directed against the structural desmosomal proteins desmoglein 1 (DSG1) and/or DSG3. Model systems allow the identification and testing of new therapeutic targets. Here, we evaluated ultrastructural desmosomal morphology in the human skin organ culture (HSOC) model injected with either anti-desmoglein (DSG) 1/3 single-chain variable fragment (scFv, termed Px4-3), Staphylococcus aureus exfoliative toxin (ETA) as a reference and positive control, and normal human IgG as a negative control. Each experimental condition was evaluated in abdominal skin biopsies from five different donors. After 24 h of incubation, we processed the samples for histological and ultrastructural electron microscopy analyses. We found that Px4-3 or ETA induced a loss of desmosomes and increased interdesmosomal widening, similar to patient skin biopsies and other pemphigus models. Thus, we propose the HSOC pemphigus model as an attractive tool to unravel novel therapeutic targets.

This study aimed to verify the role of TGFB1 variants (c.–1638G>A, c.–1347C>T, c.29C>T, and c.74G>C) in HPV infection susceptibility and cervical lesions development, and their impact on TGFB1 cervical and plasma levels. TGFB1 genotypes were assessed with PCR-RFLP and haplotypes were inferred for 190 HPV-uninfected and 161 HPV-infected women. TGFB1 levels were determined with immunofluorimetric assay. Case-control analyses were performed with logistic regression adjusted for possible confounders. Women carrying –1347TT or –1347CT+TT as well as those with 29CT, 29CC, or 29CT+CC were more likely to have HPV than –1347CC and 29TT carriers, respectively. Regarding haplotypes, the most frequent were *4 (GCTG) and *3 (GTCG). Women *4/*4 were less likely to have HPV than those with no *4 copy. Comparing the inheritance of *3 and *4, carriers of *3/*4 or *3/*3 were more susceptible to HPV than *4/*4. The TGFB1 plasma and cervical levels were higher in the infected patients. Plasma levels were also higher in infected women with low-grade lesions. HPV-infected patients carrying *3/Other and *3/Other+*3/*3 presented lower TGFB1 plasma levels than those with no copy of *3. TGFB1 variants could contribute to the comprehension of the TGFB1 role in HPV-caused cervical disease.

Complement system (CS) components are associated with Alzheimer’s disease (AD), the commonest cause of dementia in the world. Neutrophils can be attracted to amyloid-β plaques by several pro-inflammatory factors, including the complement anaphylatoxin C5a. They may release neutrophil extracellular traps (NETs), which are chromatin nets associated with myeloperoxidase, elastase, and other enzymes. Some CS molecules, such as C5a, C1q, and CR1, are associated with increased neutrophil recruitment and NETs release. However, the relationship between CS molecules and NETs in AD is poorly understood. In this work, we detected higher NET concentrations in plasma and serum of Brazilian AD patients, than in elderly controls (medians = 2.78 [2.07–6.19] vs. 2.23 [0.33–4.14] ng/mL, p = 0.0005). We discussed these results within the context of our former findings on complement and AD and the context of the literature on complement and NET release, suggesting both as possible therapeutic targets to prevent the progress of the disease.

Abstract Components of the complement system and atypical parameters of coagulation were reported in COVID-19 patients, as well as the exacerbation of the inflammation and coagulation activity. Mannose binding lectin (MBL)- associated serine proteases (MASPs) play an important role in viral recognition and subsequent activation of the lectin pathway of the complement system and blood coagulation, connecting both processes. Genetic variants of MASP1 and MASP2 genes are further associated with different levels and functional efficiency of their encoded proteins, modulating susceptibility and severity to diseases. Our review highlights the possible role of MASPs in SARS-COV-2 binding and activation of the lectin pathway and blood coagulation cascades, as well as their associations with comorbidities of COVID-19. MASP-1 and/or MASP-2 present an increased expression in patients with COVID-19 risk factors: diabetes, arterial hypertension and cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and cerebrovascular disease. Based also on the positive results of COVID-19 patients with anti-MASP-2 antibody, we propose the use of MASPs as a possible biomarker of the progression of COVID-19 and the investigation of new treatment strategies taking into consideration the dual role of MASPs, including MASP inhibitors as promising therapeutic targets against COVID-19.

Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV− patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.

The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus–human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.

Pemphigus is a group of blistering autoimmune diseases causing painful skin lesions, characterized by acantholysis and by the production of autoantibodies against, mainly, adhesion proteins. We reviewed the literature for molecules and/ or features involved in the 12 cell death pathways described by Nomenclature Committee on Cell Death, taking place in pemphigus patients, cell lines, or human skin organ cultures treated with sera or IgG from pemphigus patients or in pemphigus mouse models, and found 61 studies mentioning 97 molecules involved in cell death pathways. Among the molecules, most investigated were pleiotropic molecules such as TNF and CASP3, followed by FASL and CASP8, and then by FAS, BAX, BCL2, and TP53, all involved in more than one pathway but interpreted to function only within apoptosis. Most of these previous investigations focused only on apoptosis, but four recent studies, using TUNEL assays and/or electron microscopy, disqualified this pathway as a previous event of acantholysis. For PV, apoptolysis was suggested as a cell death mechanism based on pathogenic autoantibodies diversity, mitochondrial dysfunction, and p38 MAPK signaling. To answer those many questions that remain on cell death and pemphigus, we propose well-controlled, statistically relevant investigations on pemphigus and cell death pathways besides apoptosis, to overcome the challenges of understanding the etiopathology of pemphigus diseases.

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that occurs sporadically across the globe and is endemic in Brazil. Keratinocyte adhesion loss (acantholysis) is associated with high levels of anti-desmoglein 1 IgG autoantibodies, but the role of cell death is poorly understood in PF. Current evidence disqualifies apoptosis as the major cell death mechanism and no other process has yet been investigated. To approach the role of variation in genes responsible for cell death pathways in pemphigus susceptibility, we systematically investigated the frequencies of 1,167 polymorphisms from genes encoding products of all 12 well-established cell death cascades (intrinsic and extrinsic apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic, NETotic, lysosome-dependent, autophagy-dependent, and immunogenic). By multivariate logistic regression, we compared allelic and genotypic frequencies of 227 PF patients and 194 controls obtained by microarray hybridization. We found 10 variants associated with PF (p < 0.005), belonging to six cell death pathways: apoptosis (TNF, TRAF2, CD36, and PAK2), immunogenic cell death (EIF2AK3, CD47, and SIRPA), necroptosis (TNF and TRAF2), necrosis (RAPGEF3), parthanatos (HK1), and pyroptosis (PRKN). Five polymorphisms were associated with susceptibility: TNF rs1800630*A (OR = 1.9, p = 0.0003), CD36 rs4112274*T (OR = 2.14, p = 0.0015), CD47 rs12695175*G (OR = 1.77, p = 0.0043), SIRPA rs6075340*A/A (OR = 2.75, p = 0.0009), and HK1 rs7072268*T (OR = 1.48, p = 0.0045). Other five variants were associated with protection: TRAF2 rs10781522*G (OR = 0.64, p = 0.0014), PAK2 rs9325377*A/A (OR = 0.48, p = 0.0023), EIF2AK3 rs10167879*T (OR = 0.48, p = 0.0007), RAPGEF3 rs10747521*A/A (OR = 0.42, p = 0.0040), and PRKN rs9355950*C (OR = 0.57, p = 0.0004). Through functional annotation, we found that all associated alleles, with the exception of PRKN rs9355950*C, were previously associated with differential gene expression levels in healthy individuals (mostly in skin and peripheral blood). Further functional validation of these genetic associations may contribute to the understanding of PF etiology and to the development of new drugs and therapeutic regimens for the disease.

Skin blisters of pemphigus foliaceus (PF) present concomitant deposition of autoantibodies and components of the complement system (CS), whose gene polymorphisms are associated with susceptibility to different autoimmune diseases. To investigate these in PF, we evaluated 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients and 194 controls. After excluding SNPs with minor allele frequency

This study aimed to verify the role of TGFB1 variants (c.–1638G>A, c.–1347C>T, c.29C>T, and c.74G>C) in HPV infection susceptibility and cervical lesions development, and their impact on TGFB1 cervical and plasma levels. TGFB1 genotypes were assessed with PCR-RFLP and haplotypes were inferred for 190 HPV-uninfected and 161 HPV-infected women. TGFB1 levels were determined with immunofluorimetric assay. Case-control analyses were performed with logistic regression adjusted for possible confounders. Women carrying –1347TT or –1347CT+TT as well as those with 29CT, 29CC, or 29CT+CC were more likely to have HPV than –1347CC and 29TT carriers, respectively. Regarding haplotypes, the most frequent were *4 (GCTG) and *3 (GTCG). Women *4/*4 were less likely to have HPV than those with no *4 copy. Comparing the inheritance of *3 and *4, carriers of *3/*4 or *3/*3 were more susceptible to HPV than *4/*4. The TGFB1 plasma and cervical levels were higher in the infected patients. Plasma levels were also higher in infected women with low-grade lesions. HPV-infected patients carrying *3/Other and *3/Other+*3/*3 presented lower TGFB1 plasma levels than those with no copy of *3. TGFB1 variants could contribute to the comprehension of the TGFB1 role in HPV-caused cervical disease. [ABSTRACT FROM AUTHOR]