Activating killer cell immunoglobulin-like receptors 3DS1 and 2DS1 protect against developing the severe form of recurrent respiratory papillomatosis

Abstract

The polymorphic killer-cell immunoglobulin-like receptors (KIR) control natural killer (NK) cell response against viral infection and tumor transformation. Here we investigated if select KIR genes are associated with recurrent respiratory papillomatosis (RRP), a rare disease of the larynx and upper airway caused by human papilloma viruses (HPV)-6/11. DNA from 66 RRP patients and 195 healthy controls were characterized for KIR and HLA gene polymorphism. Patients lacking activating KIR genes 3DS1 and 2DS1 were more common in severe RRP compared to mild-moderate RRP (78.8% vs. 48.5%, p=0.019). Further, patients carrying any of the known susceptible HLA-DRB1/DQB1 alleles were more frequently negative for KIR3DS1 (p=0.006), KIR2DS1 (p=0.003) or KIR2DS5 (p=0.004) compared to controls carrying any of these HLA allotypes. Nearly 80% of the severe patients were missing the protective HLA-DQB1*0602 allele as well as both KIR3DS1 and KIR2DS1 genes. Phenotyping of papilloma-infiltrating mononuclear-cells revealed an elevated numbers of NK cells and CD57 + CD4 + T-cells in KIR3DS1 − KIR2DS1 − patients compared to patients carrying either one or both of these KIRs. Our data suggest that NK cells expressing activating receptors KIR3DS1 and KIR2DS1 may be necessary to trigger an effective early immune response against HPV-infected targets to establish resistance to RRP development.

Sequential desensitization of CXCR4 and S1P5 controls natural killer cell trafficking

“…In particular, an association between the lack of KIR3DS1 and KIR2DS1 activating NK-cell receptors and the susceptibility to recurrent respiratory papillomatosis has been reported. 38 Moreover, cases of disseminated Mycobacterium avium complex (MAC) infection have been reported in patients with a new immunodeficiency syndrome related to CXCR4 dysfunction. 39 Because these patients display a severe defect in circulating NK cells, and because MAC infections have been associated with reduced NK cell activity, 40 one can speculate that a reduction in peripheral NK-cell numbers contributes to the susceptibility to HPV and MAC infections in such leukopenic patients.…”

Papilomatosis respiratoria recurrente en paciente pediátrico: reporte de un caso

“…More recently, only results indicating a potential protective role for DQB1*0602 could be replicated by Rodier C. et al (eleven). Similarly, another study shows that about 80% of patients with severe RRP lack this protective allele 12 . An important ethnic difference has to do with the HLA-DQA*0102 allele, whose presence is associated with a high risk of developing RRP in Caucasian patients but with remission of the disease in African American patients 10 .…”

“…However, it is still unclear whether HPV causes this alteration in immunity or if children with impaired immunity develop RRP. As well as the susceptibility to cervical cancer caused by HPV has been related to some specific HLA alleles, similarly it has been seen that this association is fulfilled in patients with RRP, where certain alleles influence the course of the disease, favoring the severity [8][9][10] or, on the contrary, fulfilling a protective role 11,12 .…”

Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients

“…Activating KIR receptors have been associated with delayed progression of various diseases, including respiratory papillomatosis, human immune deficiency virus to AIDS, and Hepatitis C virus (20,23,50). A critical role for CD94/NKG2C in antiviral response was revealed in several studies performed on AIDS patients, where a natural chromosomal variation, which has a deletion of KLRC2, the gene that codes for CD94/NKG2C, was associated with increased risk of contracting HIV and more aggressive disease progression to AIDS (51).…”

“…Cytokines and viral infection may break tolerance induced by ligation of iKIRs to self-HLA, invoking potent cytolysis via the activating receptors (20,21). Hence, some activating KIRs have been associated with protection from viral infections (20,22,23) and induction of autoimmunity (24,25). Intriguingly, some autoimmune diseases are associated with reduced risk of glioma (26).…”