China
Africa
Explore chapters and articles related to this topic
The Histopathology of Eczema
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
Cynthia M. Magro, A. Neil Crowson, Molly E. Dyrsen, Martin C. Mihm
In both idiopathic erythroderma and Sézary syndrome, clonality can be seen along with certain phenotypic abnormalities including losses of CD7 and CD62L. Only biopsies of lesional tissue from Sézary syndrome patients will significantly overexpress CD158k/KIR3DL2 transcripts by reverse transcription polymerase chain reaction. Biopsies from lesional tissue of erythrodermic inflammatory conditions will not, suggesting a unique molecular marker of Sézary syndrome (Ortonne et al. 2008). The peripheral blood parameters are still critical, specifically regarding the CD4:CD8 ratio, and any phenotypic abnormalities amidst circulating T cells. A recently introduced diagnostic tool is CD27 expression on peripheral blood lymphocytes. Patients with Sézary syndrome have significantly higher expressions of the CD4+ CD27+ CD45RA–central memory T-cell subset, whereas patients with idiopathic erythroderma have increased CD4+ CD27– CD45RA–effector memory T-cell levels (Fierro et al. 2008). There are very specific peripheral blood criteria that allow one to render a diagnosis of Sézary syndrome. Multiple biopsies may be required to make the distinction (Walsh et al. 1994, Vasconcellos et al. 1995).
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].
Systematic review and meta-analytic findings on the association between killer-cell immunoglobulin-like receptor genes and susceptibility to pulmonary tuberculosis
Published in Pathogens and Global Health, 2021
Melodi Omraninava, Sahar Mehranfar, Arezou Khosrojerdi, Sirous Jamalzehi, Jafar Karami, Morteza Motallebnezhad, Mohammad Reza Javan, Saeed Aslani, Hamed Mohammadi, Ahmad Kousha
There are two haplotypes of KIR genes, including A and B that are distinguished based on variable presence of a 24 Kbp HindIII band, which later was indicated to originate from the KIR2DL5 gene [38,48]. In the haplotype A, there are KIR2DP1, KIR3DL3, KIR2DL3, KIR2DL1, KIR3DP1, KIR2DL4, KIR3DL1, KIR2DS4, and KIR3DL2 genes. The frequency of A haplotype has been estimated to be 47–59% among the Caucasians. The haplotype B contains more activating KIR genes, including KIR2DS1, KIR2DS2, KIR2DS3, and KIR2DS5, that has been reported to be highly varied. Both haplotypes contain three KIR genes, including KIR2DL4, KIR3DL2, and KIR3DL3, which are collectively called as framework loci due to pretense in all haplotypes [49]. In all haplotypes, the framework KIR3DL3 gene is located at the centromeric end, while KIR3DL2 is found at the telomeric end and KIR2DL4 is placed in the middle [50]. Several studies have implied to the role of KIR haplotypes, instead of single KIR genes, in association with diseases [51,52]. In the current meta-analysis, case-control studies evaluating the presence or absence of single specific KIR gene (regardless of the variations occurred in each gene) were included. We detected the separate association of KIR2DL3, KIR2DS1, KIR2DS4, and KIR3DL1 with PTB infection risk. The KIR2DL3, KIR2DS4, and KIR3DL1 gens are structured in the haplotype A and show LD with each other. Hence, interpretation of involvement of these KIR genes in association with PTB risk requires further analysis, in case of sufficient data available.
IPH4102, a monoclonal antibody directed against the immune receptor molecule KIR3DL2, for the treatment of cutaneous T-cell lymphoma
Published in Expert Opinion on Investigational Drugs, 2018
Carrie Van Der Weyden, Martine Bagot, Paul Neeson, Phil K. Darcy, H. Miles Prince
IPH4102 is a humanized, monoclonal antibody (mAb) directed against the immune receptor molecule KIR3DL2, produced by recombinant technology in CHO cells [31] (see Figure 1). It was selected based on its specificity toward KIR3DL2, given the absence of cross-reactivity with other members of the human killer-cell immunoglobulin-like receptor (KIR) family that share significant sequence homology. It was also preferred over other anti-KIR3DL2 mAb candidates because it binds to a particular epitope of KIR3DL2 on the D0 Ig-domain that does not result in internalization of the receptor. The persistence of the mAb-receptor complex at the surface of the targeted cells translates into optimal effector function. Drug characteristics are summarized in Box 1.
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
IPH4102 is a first-in class humanized monoclonal antibody targeting KIR3DL2, a natural killer cell receptor expressed on circulating and cutaneous Sézary cells[47]. In healthy patients, KIR3DL2 expression is limited to subsets of NK cells and CD4+ and CD8+ T cells[48,49]. In patients with MF and SS, KIR3DL2 expression was shown to be restricted to T cells with a T cell receptor TCRβ-VDJ previously identified in tumor cells[48]. Given its limited expression pattern in normal cells and specific expression in CTCL tumor cells, KIR3DL2 was proposed as a marker for CTCL tumor CD4+ lymphocytes and potential therapeutic target. IPH4102 was shown to have potent ADCC and antibody-dependent cell phagocytosis (ADCP) activity in vitro against a KIR3DL2+ CTCL cell line as well as peripheral blood mononuclear cells from eight patients with SS[50]. A phase I trial of patients with relapsed or refractory CTCL reported a global overall response in 16 out of 44 patients (36%), with 15 of those responses from 35 patients with SS[51]. The median progression-free survival was 8.2 months and the median duration of response was 18 months. Seven of the patients with Sézary syndrome had been previously treated with mogamulizumab and three of those patients achieved a global overall response with IPH4102. Treatment was associated with a decrease in Skindex-29 global scores, indicating improvement in quality-of-life measures. There was no clear correlation between baseline KIR3DL2 expression in the skin and response to IPH4102. The most common adverse events were peripheral edema (27%) and fatigue (20%). Lymphopenia occurred in 14% of patients. The TELLOMAK phase II trial is recruiting patients with refractory SS, MF, and certain subtypes of peripheral T-cell lymphoma.