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Introduction: Primarily driven by autoreactive B cells, pemphigus foliaceus (PF) is an uncommon autoimmune blistering skin disease of sporadic occurrence worldwide. However, PF reaches a prevalence of 3% in the endemic areas of Brazil, the highest ever registered for any autoimmune disease, which indicates environmental factors influencing the immune response in susceptible individuals. We aimed to provide insights into the immune repertoire of patients with PF living in the endemic region of the disease, compared to healthy individuals from the endemic region and a non-endemic area. Methods: We characterized the B-cell repertoire in i) nontreated patients (n=5); ii) patients under immunosuppressive treatment (n=5); iii) patients in remission without treatment (n=6); and two control groups iv) from the endemic (n=6) and v) non-endemic areas in Brazil (n=4). We used total RNA extracted from peripheral blood mononuclear cells and performed a comprehensive characterization of the variable region of immunoglobulin heavy chain (IGH) in IgG and IgM using next-generation sequencing. Results: Compared to individuals from a different area, we observed remarkably lower clonotype diversity in the B-cell immune repertoire of patients and controls from the endemic area (p < 0.02), suggesting that the immune repertoire in the endemic area is under geographically specific and intense environmental pressure. Moreover, we observed longer CDR3 sequences in patients, and we identified differential disease-specific usage of IGHV segments, including increased IGHV3-30 and decreased IGHV3-23 in patients with active disease (p < 0.04). Finally, our robust network analysis discovered clusters of CDR3 sequences uniquely observed in patients with PF. Discussion: Our results indicate that environmental factors, in addition to disease state, impact the characteristics of the repertoire. Our findings can be applied to further investigation of the environmental factors that trigger pemphigus and expand the knowledge for identifying new targeted and more effective therapies. [ABSTRACT FROM AUTHOR]

Pemphigus is a group of bullous diseases characterized by acantholysis and skin blisters. As for other autoimmune diseases, the strongest genetic associations found so far for pemphigus foliaceus (PF) and vulgaris (PV) are with alleles of HLA genes. However, apart from protein-coding genes, the MHC region includes a set of poorly explored long non-coding RNA (lncRNA) genes, the HLA complex group (HCG). To investigate if HCG lncRNA alleles are associated with pemphigus susceptibility. We analyzed SNPs in 13 HCG lncRNA genes, both in PV (Germany: 241 patients; 1,188 controls) and endemic PF (Brazil: 227 patients; 194 controls), applying multivariate logistic regression. We found 55 associations with PV (p corr < 0.01) and nine with endemic PF (p corr < 0.05), the majority located in TSBP1-AS1 (which includes HCG23) and HCG27 lncRNA genes, independently of HLA alleles previously associated with pemphigus. The association of TSBP1-AS1 rs3129949*A allele was further replicated in sporadic PF (p = 0.027, OR = 0.054; 75 patients and 150 controls, all from Germany). Next, we evaluated the expression levels of TSBP1-AS1 , TSBP1 , HCG23 , and HCG27 in blood mononuclear cells of Brazilian patients and controls. HCG27 was upregulated in endemic PF (p = 0.035, log 2 FC = 1.3), while TSBP1-AS1 was downregulated in PV (p = 0.029, log 2 FC = −1.29). The same expression patterns were also seen in cultured keratinocytes stimulated with IgG antibodies from patients and controls from Germany. TSBP1 mRNA levels were also decreased in endemic PF blood cells (p = 0.042, log 2 FC = −2.14). TSBP1-AS1 and HCG27 were also observed downregulated in CD19+ cells of endemic PF (p < 0.01, log 2 FC = −0.226 and −0.46 respectively). HCG lncRNAs are associated with susceptibility to pemphigus, being TSBP1-AS1 and HCG27 also differentially expressed in distinct cell populations. These results suggest a role for HCG lncRNAs in pemphigus autoimmunity. • This is the first association study investigating the whole set of HLA-Complex Group (HCG) long non-coding RNAs (lncRNAs). • TSBP1-AS1 (which includes HCG23) and HCG27 are the most strongly associated genes with pemphigus. • TSBP1-AS1 rs3129949*A allele is also associated with sporadic PF. • The HCG associations are independent of HLA alleles. • TSBP1-AS1 and HCG27 are differentially expressed in pemphigus vulgaris and pemphigus foliaceus (respectively). [ABSTRACT FROM AUTHOR]

The leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is a collagen-binding inhibitory receptor important for the regulation of immune responses, expressed on the majority of peripheral blood mononuclear cells (PBMC). LAIR-2 is a soluble homolog that antagonizes LAIR-1 inhibitory function by binding the same ligands. We sought to investigate whether LAIR1 and LAIR2 single nucleotide polymorphisms (SNP) are associated with differential mRNA expression levels. We analyzed 14 SNPs of LAIR1 (6) and LAIR2 (8) by mass spectrometry-based genotyping and extracted mRNA from PBMC of 177 healthy subjects, followed by quantitative assays. Four SNPs of LAIR1 and two SNPs of LAIR2 mark differential mRNA levels in healthy individuals. To verify the biological relevance of these findings, we analyzed additional 515 individuals (282 patients and 233 controls) to check if LAIR1 and LAIR2 differential mRNA expression could be related to susceptibility to pemphigus foliaceus (PF), an autoimmune blistering skin disease endemic in Brazil. Two LAIR1 variants (rs56802430 G, OR = 1.52, p = 0.0329; rs11084332 C, OR = 0.57, p = 0.0022) and one LAIR2 (rs2287828 T+, OR = 1.9, p = 0.0097) contribute to differential susceptibility to PF. Furthermore, we demonstrate interactions among four LAIR2 SNPs (rs2042287, rs2287828, rs2277974 and rs114834145). A haplotype harboring these SNPs is strongly associated with higher LAIR2 mRNA levels (4.5-fold, p = 0.0069) and with higher susceptibility to PF (OR = 4.02, p = 0.0008). We suggest that LAIR1 and LAIR2 genetic variants are associated with regulation of gene expression and variable PF susceptibility, and show indirect association of LAIR2 differential mRNA expression with PF pathogenesis. Our data demonstrate how this relatively unknown disease can add invaluable knowledge regarding the role of LAIR1 and LAIR2 in immune responses.

Births were observed in two free-ranging groups of red-handed howlers (Alouatta belzebul) in eastern Brazilian Amazonia. Both events occurred in the early afternoon, and were relatively rapid and discrete. No other group members approached the females during parturition, nor attempted to interfere with the neonate in any way. Only one of the mothers ingested the placenta. This same female carried the neonate ventrally during the first month of life and then it was carried dorsally. The other infant was carried by its mother in a dorsal position from birth onward. Both infants survived their first month, but subsequently disappeared, in the second and fourth months of life. The precise causes of their death are unknown. In one case, we speculate that the infant's death was due to infestation by botfly larvae., (Copyright 2007 Wiley-Liss, Inc.)

Two tayras (Eira barbara) were observed attacking an infant red-handed howler (Alouatta belzebul) on an island in eastern Brazilian Amazonia, as a nearby adult male watched passively. In a separate incident, four tayras were seen attacking a subadult female on the ground. Tayras were also observed in the vicinity of the two howler study groups on a number of occasions over a 9-month period. During this same period, the two groups lost a third of their members, including infants and subadults, and the remains of six animals were found at the study site. While tayras were the only predators seen attacking the howlers, it remains unclear to what extent they were responsible for apparently high mortality rates in this high-density, isolated howler population.

Mammalian seasonal molting and color change are known to be influenced by photoperiod changes. Calomys laucha, a South American rodent, exhibits seasonal pelage color change; however, unlike Northern hemisphere rodents, which present a gray or brown color during summer and a whitish color during winter, C. laucha pelage changes from an orange color during summer to a dark gray color during winter. Animals maintained for over a year in stationary photoperiod (LD 12:12h, 22 degrees C) presented orange pelage color during the summer corresponding month (January), and gray color during the winter corresponding month (July). Same age animals were evaluated during summer or winter months, and also showed different colors. Animals exposed for 12 weeks to summer or winter artificial conditions displayed color change, not according to the environmental conditions, as expected, but similar to that of animals maintained in stationary photoperiod. These results suggest that pelage color change in C. laucha is controlled by an endogenous circannual rhythm. The adaptive function of C. laucha color change is discussed.