The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Abstract

Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and b-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.

The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat

“…However, Hse1 was confirmed as the main disease regulating region by infecting congenic lines. The antigen-presenting lectin-like receptor gene complex (APLEC) located towards the end of chromosome 4 was previously reported to have a disease regulatory effect in a different model of HSV-1-induced encephalitis in the DA strain [15]. However, in this present study by infecting R17 congenic [24] rats with HSV-1, we could not confirm any HSE regulation by the APLEC genes region.…”

“…None of the rats developed symptoms, demonstrating the protective role of the PVG alleles in the Hse1 region (Figure 3). For both mapping and control purposes, we furthermore tested HSE susceptibility in a set of congenic lines with different chromosome 4 congenic PVG fragments on the DA background; R2:DA.PVG (D4Rat23–D4Rat108), R11:DA.PVG (D4Rat103 – D4Mit12), R21:DA.PVG (OT40.07 – D4Mit12) covering the experimental autoimmune encephalomyelitis (EAE) QTLs Eae24–Eae27 [14] and R17 (D4Kiru12–D4Kiru55) covering the APLEC genes region that are associated with arthritis and autoimmunity in rats and humans [15] (Figure 3). All of these lines are homozygous for DA alleles in Hse1 .…”

Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus

“…Especially the increased TNFa production stands in discrepancy to other studies, where TNFa appears to be a mediator of joint inflammation. 23 However, our findings are in agreement with data from Guo et al, 24 where they found an enhanced IL-6 secretion of Oia2 congenic macrophages following LPS stimulation. It also confirms data from a mutant DA rat, which is protected from PIA, CIA and experimental allergic encephalomyelitis yet shows enhanced cell proliferation and Th1 cytokine production as well as an increased number of activated T cells (unpublished data).…”

A Replication Study Confirms the Association of Dendritic Cell Immunoreceptor (DCIR) Polymorphisms with ACPA - Negative RA in a Large Asian Cohort

“…Its precise role and function are not completely understood, but we and others have previously identified a cluster of C-type lectin receptor genes including DCIR that regulates arthritis susceptibility and influences the development of infectious diseases in rat [11], [12]. DCIR knockout (DCIR-KO) mice showed a markedly exacerbated response to collagen-induced arthritis, and aged DCIR-KO mice spontaneously developed sialadenitis and enthesitis with elevated levels of autoantibodies [13].…”