The multiple roles of major histocompatibility complex class-I-like molecules in mucosal immune function

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class-I genes: human leukocyte antigens (HLA) A, B, and C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa β₂-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed, polymorphic proteins, the human genome also encodes several nonclassical MHC class-I-like, or class Ib, genes that, in general, encode nonpolymorphic molecules involved in various specific immunological functions. Many of these genes, including CD1, the neonatal Fc receptor for IgG, HLA-G, HLA-E, the MHC class-I chainrelated gene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.     

Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance

Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn’s disease are those related to bacterial sensing, such as through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance.     

Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5^−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.     

Coronavirus disease 2019: Implications of emerging infections for transplantation

The recent identification of an outbreak of 2019‐ novel Coronavirus is currently evolving, and the impact on transplantation is unknown. However, it is imperative that we anticipate the potential impact on the transplant community in order to avert severe consequences of this infection on both the transplant community and contacts of transplant patients.     

Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice

BACKGROUND & AIMS: CD1d is a major histocompatibility complex class I-like molecule that presents glycolipid antigens to a subset of natural killer (NK)1.1(+) T cells. These NK T cells exhibit important immunoregulatory functions in several autoimmune disease models. METHODS: To investigate whether CD1d and NK T cells have a similar role in intestinal inflammation, the effects of the glycolipid, alpha-galactosylceramide (alpha-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/-), and RAG(-/-) mice were examined for their response to either alpha-GalCer or the control analogue, alpha-mannosylceramide (alpha-ManCer). RESULTS: WT mice, but not CD1d(-/-) and RAG(-/-) mice, receiving alpha-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving alpha-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of alpha-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by alpha-GalCer, but not alpha-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of alpha-GalCer, confocal microscopy localized alpha-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating alpha-GalCer binds CD1d in the intestinal epithelium and may be functionally active at this site. CONCLUSIONS: These results show an important functional role for NK T cells, activated by alpha-GalCer in a CD1d-restricted manner, in regulating intestinal inflammation.