https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-6143.2003.00135.x

Humoral Theory of Transplantation

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.

/pdf/distinguishing-functional-polymorphism-from-random-variation-1rki8bmpmi.pdf

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

Many common disorders, including such scourges of Western society as ischaemic heart disease' and many forms of cancer,2 result in part from heritable factors. Of particular interest to the rheumatologist is the group of complex, multifactorial, polygenic disorders comprising the 'autoimmune diseases', of which rheumatoid arthritis (RA) is probably the commonest. Similarities between this form of inflammatory arthritis and others, known to be triggered by infectious agents, have inevitably fuelled speculation that RA may have a similar cause. To date, however, the identification of infectious triggers has been conspicuously lacking. In contrast, over the past two decades there has been considerable progress in identifying at least some of the genetic factors contributing to susceptibility to RA. Thus the immune response genes of the HLA class II region of the major histocompatibility complex (MHC) are quite clearly implicated in the pathogenesis of this condition, though their precise role is, as yet, unclear.

https://ard.bmj.com/content/annrheumdis/50/6/343.full.pdf

Polygenic susceptibility in rheumatoid arthritis.

Blood transfusion results in significant alterations in some parameters of immune function. Because some human cancers appear to stimulate immune responses and may be influenced by host immunity, the possibility arises that transfusion could alter the behaviour of tumours. Experimental studies indicate that allogeneic transfusion can directly alter tumour growth in some circumstances, but at present studies of human cancers do not provide evidence of a causal association between transfusion and tumour growth.

Relationship between blood transfusion and tumour behaviour.

The association between HLA-DR4 and rheumatoid arthritis (RA) has been established in many ethnic groups. To clarify the determinant of susceptibility to RA, a polymorphic segment of the HLA-DRB gene was amplified in vitro by polymerase chain reaction and analyzed with oligonucleotide probes specific for the HLA-DR4 DNA sequences. A particular sequence encoding amino acids Gln70-Arg71-Arg72-Ala73-Ala74 showed a strong association with RA (p less than 0.005, relative risk 6.0). This amino acid sequence occurs in the DRB molecules with three RA-associated specificities, DR4/Dw14, DR4/Dw15, and DR1. DR4/Dw4, which is common in Caucasian RA patients, has a strikingly similar amino acid sequence Gln70-Lys71-Arg72-Ala73-Ala74 in terms of polarity and charge profiles. Other RA nonassociated sequences differ from this sequence by at least one amino acid substitution that causes the change of the net charge. The composition of amino acid residues at the positions 70-74 may play a crucial role in the pathogenesis of RA.

/pdf/putative-amino-acid-sequence-of-hla-drb-chain-contributing-vg39hdta1a.pdf

Putative amino acid sequence of HLA-DRB chain contributing to rheumatoid arthritis susceptibility.

We tested HLA-DR antigens in 38 Caucasian, 18 Negro, 17 Mexican, and 5 Japanese patients with rheumatoid arthritis. Significantly high HLA-DR4 frequencies were observed in all races; 61% in Caucasians, 39% in Negroes, 77% in Mexicans, and 100% in Japanese. However, no clinical correlation with DR4 was found in these patients.

HLA-DR4 in Negro and Mexican rheumatoid arthritis patients.

1. Out of 122 sera from patients who had rejected a kidney transplant, 82% had cytotoxic antibodies to HLA. These antibodies were present in about equal frequency regardless of when the graft was rejected. Twelve patients who had rejected their grafts after 5-15 years also produced clear HLA antibodies. 2. The HLA antibodies were not directed to all the mismatches of the donor, but rather appeared to be against a few of the specificities. Thus the graft could have been rejected by a response directed at a few major determinants. Antibodies to some antigens were not detected at all. 3. Some patients produced their HLA antibodies many months after the rejection of their first graft.

Sensitization after transplantation.

Thirty families in whom at least one member had asthma were typed for five new B-lymphocyte specificities, as well as the antigens of the A and B loci of HLA. The B-cell reactions were consistent with the concept that they were determined by genes linked to the HLA-A and HLA-B loci. Between 22 HLA-identical siblings and 16 two-haplotype different siblings, a significant difference in concordance of reactions for the B-cell groups was noted. The data obtained were most compatible with B-groups 1 and 2 being determined by one locus and B-groups 3, 4, and 5 by another locus. The superhaplotypes of HLA-A, HL-B, and B-cell loci 1 and 2 were then determined. The most striking linkages noted were for the second B-cell locus and the HLA-B locus: B-cell group 3 with HLA-B12, B-cell group 4 with HLA-B7, and B-cell group 5 with HLA-B8, B17, and Bw35.

B-lymphocyte haplotypes in asthma families.

1 The 3-month actual graft survival of 6-antigen matched transplants in the UNOS program was 96% compared to 85% in control kidneys which were not shipped (p = 0004) Actuarial graft survival at 1 year was 89% for the 6-antigen matched kidneys and 78% for the controls (p = 002) 2 Several individual centers reported 1-year graft survival rates of 85-95% (in the first half of this volume) Various immunosuppressive protocols and attention to patient care resulted in high 10-year survival of 53% in 1 instance (Leuven) 3 The 1-year graft survival peaked at about 77% for transplants performed in 1985, 1986, and 1987 4 Among transplants performed since 1984, HLA matching of cadaver donor transplants showed a 13% difference at 1 year between the best and worst A,B,DR matches, which expanded in 3 years to an 18% difference 5 The center effect, which produces about a 13% difference in 1-year graft survival for cadaver donors, decreased to 0 in HLA-identical transplants Thus, when the donor and recipient were histocompatible, all centers were able to achieve superior results The results of the 6-antigen Match Study appear to validate this conclusion 6 Preformed antibody is associated with a 9% decrease in graft survival for greater than 50% PRA in first grafts and 4% in second grafts For peak antibodies, the difference was 7% for first grafts and 11% for second grafts 7 Platelet flow cytometry in 23 patients with a positive flow cytometry crossmatch to T cells furnished a further refinement in grouping the patients All 11 patients with a negative platelet crossmatch had functioning grafts at 1 month whereas only 5 of 12 patients with a positive platelet crossmatch had a functional graft at 1 month (p = 0003) 8 The duration of first graft effect on the second graft has diminished considerably as immunosuppression improved Patients whose first graft survived more than a year and who had a high 1-year graft survival of the second graft lost their second graft at an accelerated rate after the first year At the end of 4 years, their survival was the same as that of the responder patients who had rejected their first grafts within 3 months 9 False positive crossmatches, especially in "highly" sensitized patients were identified by the use of DTT Transplants into 69 patients who were positive by the standard test but negative after DTT had a 94% 1-month function rate(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical transplants 1988. Overview.

A total of 950 MLC combinations were set up out of which 259 were classified as low MLC response. An attempt was made to predict which of the combinations would give low response by matching the B-lymphocyte specificities and the HLA-A and -B antigens. A statistically significant prediction of a low response was noted for the B-lymphocyte specificities as well as for HLA-A and -B antigens. The fraction of the low response, which was correctly found, was, however, greater with the B-cell specificities than the HLA-A and -B locus antigens. It is concluded that the B-lymphocyte specificities may be either identical or closely linked to the DW specificities. To what extent they are associated with the strong transplantation antigens of man remains to be determined.

The role of B-lymphocyte antigens in MLC stimulation.

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