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Genetics of Psoriasis and Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
The best evidence for the involvement of adaptive immunity in PsA comes from the association with HLA-B*27; however, the pathogenic role of B*27 in PsA remains unclear. Hypotheses regarding its role include the arthritogenic peptide hypothesis, the B*27 misfolding hypothesis, and the B*27-free heavy-chain and homodimer hypothesis [170–172]. The arthritogenic peptide hypothesis postulates that B*27 binds and presents shared arthritogenic peptides from disease-causing pathogens to CD8+ T cells, and these peptides are also cross-reactive to a self-peptide that can also be bound and presented by B*27. If this binding is mediated by particular amino acid residues contained within the HLA-B binding pocket, such as Glu45, this might explain the strong association with Glu45 and the alleles B*27, B*38, and B*39 [50]. However, no arthritogenic peptides have been identified in PsA, and animal studies suggest that CD8+ T cells are not required for disease [173]. The misfolding hypothesis postulates that misfolded B*27 heavy chains accumulate in the endoplasmic reticulum, chronically stimulating a stress response that leads to the release of inflammatory cytokines that trigger the innate immune response [172]. Some animal studies support this hypothesis [174], whereas others have shown that reversal of the accumulation of misfolded heavy chains has no effect on disease phenotype [175]. The B*27-free heavy-chain and homodimer hypothesis postulates that both the innate and adaptive immune systems are triggered by misfolded B*27 molecules on the cell surface via their interactions with various immunoregulatory receptors, which could include the KIRs and/or the leukocyte immunoglobulin-like receptors (LILRs) [170–172]. This theory is supported by the finding of an enrichment of KIR3DL2+ CD4+ T cells producing IL17 after stimulation with B*27 homodimers in the peripheral blood and synovial fluid of PsA patients [176].
LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs
Published in OncoImmunology, 2022
Mei-Tzu Su, Sakiko Kumata, Shota Endo, Yoshinori Okada, Toshiyuki Takai
Myeloid-derived suppressor cells (MDSCs), a population of immune suppressive cells, strongly inhibit anti-tumor immune reactions mediated by T cells and enhance angiogenesis for metastatic formation.4 MDSCs consist of two major subsets in human and mice, monocytic-MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC), also known as granulocytic MDSC (G-MDSC).5 Both MDSC subsets are found in the bone marrow, spleen, lung, peripheral blood, and tumor tissue.6 MDSCs are capable of polarizing to a classically activated (M1) or an alternatively activated (M2) phenotype. M1 MDSCs exhibit anti-tumor activities by secreting tumor necrosis factor (TNF-α) and nitric oxide (NO); whereas M2-polarized MDSCs suppress effector T cells (Teff) but activate regulatory T cells (Treg) through the expression of interleukin-10 (IL-10), transforming growth factor (TGF-β) and arginase-1 (ARG1).7,8 Several studies have shown that MDSCs infiltrated in various cancers, both in the primary tumor and metastatic sites.9 MDSC-mediated immunosuppression limits the potency of cancer immunotherapy drugs, such as anti-programmed death receptor-1 (PD-1), anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4);10,11 therefore, targeting tumor-infiltrating MDSCs is an important issue in cancer therapy. Interestingly, the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) is expressed on MDSCs and correlates with survival in human lung cancer patients.12
Innate immunity: Trained immunity and innate allorecognition against the allograft
Published in International Reviews of Immunology, 2022
Mohammad Mirzakhani, Mehdi Shahbazi, Sara Shamdani, Sina Naserian, Mousa Mohammadnia-Afrouzi
PIRs-MHC I axis is another pathway contributing to innate allorecognition. PIRs are immunoglobulin-like receptors and consist of PIRs A and B, which are expressed on various immune cells, including monocyte, macrophage, and DC.35 At least six genes for the PIRA proteins and one gene for the PIRB protein have been identified in mouse chromosome 7, which bind to MHC-I molecules. PIRAs contain immune-receptor tyrosine-based activation motifs (ITAMs) that send stimulatory signals, whereas PIRB has ITIMs that inhibit cell activation.35 In the human body, leukocyte immunoglobulin-like receptors (LILRs) are orthologs of mouse PIRs and include six LILR-As and five LILR-Bs. LILR-As and LILR-Bs bind to the broad-spectrum of MHC-I molecules and send stimulatory and inhibitory signals, respectively.35–38
TIM-3 pathway dysregulation and targeting in cancer
Published in Expert Review of Anticancer Therapy, 2021
Amer M Zeidan, Rami S Komrokji, Andrew M Brunner
In MDS and AML, immune checkpoint therapy targeting the classic pathways of CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) and PD-L2 has so far only shown limited clinical activity as monotherapy [78,82–86] while early-phase trials are ongoing as combination therapy with additional checkpoint inhibitors, hypomethylating agents (HMAs), or intensive chemotherapy [87,88]. The only randomized clinical trial of checkpoint inhibition in myeloid malignancies combined the anti–PD-L1 antibody durvalumab with azacitidine as frontline therapy in patients with higher-risk MDS and in older patients with AML unfit for intensive chemotherapy; no improvements were reported in response rate or survival compared with the results of azacitidine monotherapy in either cohort [89]. Notably, however, PD-1 blockade following stem cell transplant in AML may enhance the graft-versus-leukemia effect and T-cell function [90]. Although it is clear that immuno-oncologic therapeutics have not yet revolutionized the hematologic malignancy treatment landscape as in solid tumors, the clinical success of stem cell transplant in myeloid malignancies demonstrates the potential of immunotherapeutic modalities in these diseases in particular [13,91–93]. Other immune checkpoint pathways involving receptors such as TIM-3, lymphocyte activation gene 3, CD47, and leukocyte immunoglobulin-like receptor 4 may be more relevant to the pathogenesis of myeloid malignancies; therefore, their targeting could prove to be more therapeutically active [94].