A man dies because his body has rejected a heart transplant; a woman is crippled by rheumatoid arthritis; a child goes into a coma that is brought on by cerebral malaria; another child dies of an infection because of an immunodeficiency; an elderly man has advanced hepatic cirrhosis caused by iron overload. These five clinical situations are as diverse as can be, yet all have one thing in common: the cause of all of them involves the human leukocyte antigen (HLA) system, the human version of the major histocompatibility complex (MHC). Malfunction of the HLA system, which is at the . . .

The HLA system. First of two parts.

The HLA system. Second of two parts.

Susceptibility to multiple sclerosis is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 (DRB1*1501) haplotype. The structure of HLA-DR2 was determined with a bound peptide from human myelin basic protein (MBP) that is immunodominant for human MBP-specific T cells. Residues of MBP peptide that are important for T cell receptor recognition are prominent, solvent exposed residues in the crystal structure. A distinguishing feature of the HLA-DR2 peptide binding site is a large, primarily hydrophobic P4 pocket that accommodates a phenylalanine of the MBP peptide. The necessary space for this aromatic side chain is created by an alanine at the polymorphic DRβ 71 position. These features make the P4 pocket of HLA-DR2 distinct from DR molecules associated with other autoimmune diseases.

https://rupress.org/jem/article-pdf/188/8/1511/1119202/98-1219.pdf

Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein

Human T-cell-mediated autoimmune diseases are genetically linked to particular alleles of MHC class II genes. Susceptibility to pemphigus vulgaris (PV), an autoimmune disease of the skin, is linked to a rare subtype of HLA-DR4 (DRB1*0402, 1 of 22 known DR4 subtypes). The PV-linked DR4 subtype differs from a rheumatoid arthritis-associated DR4 subtype (DRB1*0404) only at three residues (DR beta 67, 70, and 71). The disease is caused by autoantibodies against desmoglein 3 (DG), and T cells are thought to trigger the autoantibody production against this keratinocyte adhesion molecule. Based on the DRB1*0402 binding motif, seven candidate peptides of the DG autoantigen were identified. T cells from four PV patients with active disease responded to one of these DG peptides (residues 190-204); two patients also responded to DG-(206-220). T-cell clones specific for DG-(190-204) secreted high levels of interleukins 4 and 10, indicating that they may be important in triggering the production of DG-specific autoantibodies. The DG-(190-204) peptide was presented by the disease-linked DRB1*0402 molecule but not by other DR4 subtypes. Site-directed mutagenesis of DRB1*0402 demonstrated that selective presentation of DG-(190-204), which carries a positive charge at the P4 position, was due to the negatively charged residues of the P4 pocket (DR beta 70 and 71). DR beta 71 has a negative charge in DRB1*0402 but a positive charge in other DR4 subtypes, including the DR4 subtypes linked to rheumatoid arthritis. The charge of the P4 pocket in the DR4 peptide binding site therefore appears to be a critical determinant of MHC-linked susceptibility to PV and rheumatoid arthritis.

https://www.pnas.org/content/pnas/92/25/11935.full.pdf

Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris.

Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. In both diseases, the autoantigens have been cloned and characterized; pemphigus antigens are desmogleins (cell adhesion molecules in desmosomes), and pemphigoid antigens are found in hemidesmosomes (which mediate adhesion to the basement membrane). This knowledge has enabled diagnostic testing for these diseases by enzyme-linked immunosorbent assays and dissection of various pathophysiological mechanisms, including direct inhibition of cell adhesion, antibody-induced internalization of antigen, and cell signaling. Understanding these mechanisms of disease has led to rational targeted therapeutic strategies.

/pdf/mechanisms-of-disease-pemphigus-and-bullous-pemphigoid-5fl46wzi4a.pdf

Mechanisms of Disease: Pemphigus and Bullous Pemphigoid.

Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.

Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris.

Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes.

Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

Introduction: Glioblastoma Multiforme (GBM) is the most aggressive brain tumour with a dismal prognosis. Very few studies on its diagnosis, prognosis and therapeutics have been attempted in the past on Indian population. Standard treatment of this highly aggressive tumour yields little survival benefit; hence, greater attention is now being paid to personalised treatment and, correspondingly, to the expression of specific molecular markers with the goal of assessing their possible therapeutic as well as prognostic significance. Aim: To estimate the proportion of Tumour Protein 53 (TP53) and PTEN (Phosphatase and Tensin Homolog) expression in GBM patients of Western Rajasthan, India. Materials and Methods: This study was a ambispective, single institutional observational study done on 35 brain tissue biopsies of histopathologically diagnosed and confirmed cases of GBM based on the World Health Organisation (WHO) classification, 2007 received in Department of Pathology, Dr. Sampurnanand Medical College (Dr. SNMC), Jodhpur, Rajasthan, India, from January 2015 to December 2020 (January 2015 to September 2018 Retrospective and October 2018 to December 2020 Prospective) after applying inclusion and exclusion criteria. Immunohistochemical (IHC) analysis was done for TP53 and PTEN markers in all cases of GBM. The results were then applied for statistical analysis using Statistical Package for the Social Sciences (SPSS) version 22.0 software package (SPSS Inc., Chicago, IL, USA). The association between age and gender with TP53 and PTEN positive cases, respectively, was analysed by using Fisher’s-exact test and the results of the same were compiled. Results: TP53 expression was seen in 32 cases (91.4%). The mean age of presentation of TP53 positivity was 50.3 years. Most of the TP53 cases occurred in the 41 to 50 and 61 to 70 years of age groups. In TP53 mutated cases, males were found more commonly affected as compared to females. Overall, the majority of cases (eight cases) occurred in the temporal region of the brain (25%). The relationship between age and gender with TP53 expression was found to be insignificant. PTEN expression was found absent (mutation positive) in 11 cases (32.4%). Mean age of these patients was 52.5 years. The male to female ratio was found to be 1.8:1. Regarding tumour location in the brain, most of the cases occurred unilaterally, with 45.4% (n=5) of cases occurring in the temporal region. The association between PTEN mutation with age and gender was not found to be significant. Conclusion: The higher prevalence of TP53 expression in the population suggests distinct genetic pathways that need to be studied in detail to have a better understanding of this highly aggressive tumour. The PTEN mutation was discovered to be prevalent in the population of Western Rajasthan and needs to be studied further on a large scale. The simultaneous presence of molecular markers in GBM cases would need to be considered before initiating any gene therapy for its improved effectiveness.

K Khatri

Papers

Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris.

Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

Immunohistochemical Analysis of TP53 and PTEN Expression in Glioblastoma Multiforme Patients of Western Rajasthan, India: An Observational Study