Clinical and immunological aspects of HLA class I deficiency

Abstract

Human leukocyte antigen (HLA) class I deficiency is a rare disease with remarkable clinical and biological heterogeneity. The spectrum of possible manifestations extends from the complete absence of symptoms to life-threatening disease conditions. It is usually diagnosed when HLA class I serological typing is unsuccessful; flow cytometric studies then reveal a severe reduction in the cell surface expression of HLA class I molecules (90-99% reduction compared to normal cells). In most cases to date, this low expression is due to a homozygous inactivating mutation in one of the two subunits of the transporter associated with antigen processing (TAP), critically involved in the peptide loading of HLA class I molecules. Although asymptomatic cases have been described, TAP deficiencies are usually characterized by chronic bacterial infections of the upper and lower airways, evolving to bronchiectasis, and in half of the cases, also skin ulcers with features of a chronic granulomatous inflammation. Despite the defect in HLA class-I-mediated presentation of viral antigens to cytotoxic T cells, the patients do not suffer from severe viral infections, presumably because of other efficient antiviral defence mechanisms such as antibodies, non-HLA-class-I-restricted cytotoxic effector cells and CD8+ T-cell responses to TAP-independent antigens. Treatment is at present exclusively symptomatic, and should particularly focus on the prevention of bronchiectasis, which requires early detection.

A novel approach to analyze gene expression data demonstrates that the ΔF508 mutation in CFTR downregulates the antigen presentation pathway

“…A rare genetic disorder, TAP (transporter associated with antigen presentation) deficiency, abrogates MHC class I antigen presentation and causes rhinosinusitis, chronic lung infection, and bronchiectasis (6), reminiscent of CF. TAP-deficient patients also experience opportunistic infection by Pseudomonas (52). Macrophages, present in the lungs and isolated by lavage, but not monocytes circulating in the bloodstream, also have defective antigen presentation in late-stage CF patients (24), perhaps accounting for the observation that CF patients generally mount a normal immune response except in the lungs.…”

NK Cells in Central Nervous System Disorders

“…By using a mouse model of HSV1 encephalitis, Adler et al (28) directly demonstrated that NK cells have an important role in the defense against this severe form of infection. Nonetheless, TAP-deficient patients known to have hyporesponsive NK cells rarely present with viral encephalitis (29). In contrast, TLR3-deficient patients are susceptible to HSV encephalitis, and they present impaired NK cell IFN-g secretion following stimulation with polyinosinic-polycytidylic acid, but normal production against K562 (30), suggesting that TLR3 dysfunction could be at the origin of this disease phenotype.…”

Immunity to Microbes: Lessons from Primary Immunodeficiencies

“…This contrasts with classical observations of murine models (120) which demonstrate that antiviral defense is ensured by class I-restricted CD8 ϩ T cells. Thus, patients with low levels of expression of MHC-I molecules (transporters associated with antigen processing 1 [TAP-1], TAP-2, and tapasin deficiencies) (47,69,73,115,119), as well as those with low numbers of cytotoxic CD8 ϩ ␣␤ T cells (inherited CD8 deficiency) (28), are not particularly susceptible to viral diseases. Equally surprising, patients with either TAP deficiencies or familial CD8 deficiency due to a mutation in the CD8␣ gene (28,32,45,47).…”

“…Their serology was also positive for live-vaccine viruses, such as polioviruses, measles, and mumps. While a respiratory viral infection might have preceded bacterial disease, as in patients with antibody deficiencies, it remains surprising that the clinical manifestations of MHC-I/CD8 deficiencies resemble those of humoral deficiencies (28,32,65,69,119). Along the same lines, perforin defects do not seem to impart increased susceptibility to viral infections (41,71).…”