Human Leukocyte Antigen (HLA) part 76

hla protein 1

 

In humans, tumours alterations in the surface expression and/or function of HLA class I antigens are frequently found and equipt neoplastic cells with mechanisms to escape immune control. The aberrant expression of HLA class I molecules can be caused by structural alteration or dysregulations of genes encoding the classical HLA class I   antigens and/or components of the HLA class I APM. The dysregulation of APM components  could occur at the epigenetic, transcriptional or post-transcriptional level. Interestingly, none of the HLA class I and II alleles  have been demonstrated to be associated with an inctreased incidence per se of any cancer. However, individual alleles are known  to be overrepresented in certain cancers or  correlate with survival, prognosis, higher tumour staging, grading, disease progression and failure to CD8 T cells based immunotherapies.

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Human Leukocyte Antigen (HLA) part 75

hla protein 1

 

HLA AND CANCER

The theoritical model, which explains the manner through which there is unrestrained growth of cells that are different from those of the tissue from which they originate, is based on the modification of surface molecules that determine the recognition of celf-cells by the immunes ystem. Tumour cells do not respond to the regulatory stimuli that normally limit tissue proliferation. Carcinogens and oncogenic viruses activate gens that destabilize cell proliferation and repair. As a result, some cell-surface antigens are lost and others are expressed. At the end of this process, the tumour may no longer be recognized by the immune system. Structural and functional changes in HLA, loss of expression of tumour antigens, lack of co-stimulatory molecules and production of immunosuppresive cytokines are some of the possible mechanisms that cause tumour cells to escape immune surveillance.

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Human Leukocyte Antigen (HLA) part 74

hla protein 1

 

Both HLA-B27 and HLA-57 have been identified in terms both HIV and HCV infection. The mechanisms  for this joint efficacy could be manifold. First, it is possible that both HLA alleles could be in linkage disequilibrium with other genes in the major histocompatibility complex which are more directly responsible for their effects. Second,  it is possible that both HLA molecules select for epitopes that may have an influence on viral fitness. Third, it is possible that such associations are simply related to the prevalence of a particular gene in a population  because it is likely that in any given population there will be less exposure to and consequently less selection against, rare alleles, particularly in population where the prevalence of the condition has increased recently. It is worth noting that there are also striking differences between HIV and HCV in HLA types association with protection.

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Human Leukocyte Antigen (HLA) part 73

hla protein 1

 

Hepatitis C Virus (HCV)

HLA associations with respect to hepatitis B virus and HCV infection susceptibility, protection, disease severity, interferon treatment  response and response to vaccination have been intensively investigated across the global population. The associations between HLA class I antigens and the outcome of HCV infection are are extensively investegated in different ethnic populations, and the reported associations showed ethnic and geographical differences sometimes with contradictory results. In the same time, there is a striking concordance between several of the HLA alleles associated with clearance   in both HIV and HCV infection including, in particular, HLA-B27. Other associations with HLA-B57 and HLA B08DR3 are less consistent  and may relate to differences in viral sequences in certain subpopulations.

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Human Leukocyte Antigen (HLA) part 72

hla protein 1

 

Moreover, recent study by Elahi and Horton provided novel insights into the role of T regs in chronic viral infection. This study showed that HIV-specific CD8 T cells restricted by protective HLA-B27/B57 alleles are much more resistant to T reg-mediated suppression than CD8 T cells restricted by non-protective HLA alleles. This resistence to T reg suppression was because CD8 T cells restricted by protective HLA alleles upregulated low levels of T cell immunoglobulin Mucin Protein-3 where they encountered their antigen. Thus, T regs were not able to suppress  proliferation of these HIV-specific CD8 cytotoxic T lymphocyte through Tim-3:Galactine-9 interaction. In contrast, HIV-specific CD8 cytotoxic T lymphocyte restricted by non-protective allels upregulated high levels of Tim-3 when they encountered their antigen and were subsequently suppressed by  T regs. The lack of suppression of B27/B57-restricted cytotoxic T lymphocyte allows them to continue to proliferate and kill infected targets during chronic infection, which may account for delayed disease progression in persons with protective alleles

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Human Leukocyte Antigen (HLA) part 71

hla protein 1

 

Therefore, there must be additionally immunological mechanisms that contribute to the protective effect of these HLA alleles in HIV and HCV infection. Several  immunological mechanisms have been suggested contributing to protection by HLA-B-27 including CD8 T cell polyfunctionality (indicated by simultaneous  production of multiple antiviral cytokines) and functional avidity (the sensitivity of CD8 T cells to antigenic stimulation), thymic selection of CD8 T cell precursor (HLA class I alleles that bind few  self-peptides are associated with a greater CD8 T cell precursor   \repertoir and broader cross-reactivity of CD8 T cells, finally leading to superior viral control), specific T cell receptor repertoirs and clonotypes (the selection of T cell receptor clonotypes impact antiviral efficacy and the capacity  to cross-recognize viral variants and in HCV, limited  T cell receptor diversity has been linked to the evolution of viral escape mutations), efficient antigen processing (the amount of peptide produced by the antigen-processing machinery  correlated with magnitude  and requency of HIV and HCV-specific CD8 T cells responses) and evasion from T reg suppression (T regs are thought to suppress HIV and HCV-specific CD8 T cells) and thus contribute to CD8 T cell exhaution snd failure. It has been demonstrate, however, that HIV-specific CD8 T cells restricted by the protective HLA alleles B27 and B57 are not suppressed by T regs

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Human Leukocyte Antigen (HLA) part 70

hla protein 1

 

Kaslow et al. assesed the role of HLA class I alleles in HIV infection and found that HLA-B27 and B57 were strongly associated with slow progression to AIDS. Importantly, several independent studies have confirmed this finding, including a recent study that included more than 2700 patients with HIV infection. It is important to note, however, that HLA-B27 and B57 are not unique in their association with HIV control, but are rather extremes in an continuous spectrum of “protective” to “hazardous” HLA class I alleles. HLA-B27 is associated with low viral load and long-term non-progression in HIV infection as well as spontaneous clearance of hepatitis C infection. Recent studies  linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as  complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD 8 T cell epitopes. This virological mechanisms may help to explain why CD8 T cell responses targeting certain  HIV and HCV-specific epitopes contribute to protection. However, they cannot explain why largely the same HLA class I alleles, including HLA-B27 and HLA-B57, are protective in unrelated viral infections.

 

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