J A López de Castro

Peptides: the cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis

The association of human leukocyte antigen (HLA)-B27 to ankylosing spondylitis is one of the strongest between a major histocompatibility complex molecule and a disease. Yet, the basis for this association remains unknown. Several hypotheses, each based on a particular feature of HLA-B27, guide much of the current research on the pathogenesis of this disease, but none has yet satisfactorily explained its mechanism and the differential association of B27 subtypes to it. In this review, the pathogenetic role of HLA-B27 will be analyzed from a global perspective of its biology, emphasizing the interdependency of multiple molecular features and the likely influence of disease-modifying gene products. From this perspective, peptide binding emerges as the cornerstone of all other biological properties.

A high incidence of Shigella-induced arthritis in a primate species: major histocompatibility complex class I molecules associated with resistance and susceptiblity, and their relationship to HLA-B27

Abstract The human major histocompatibility complex (MHC) class I gene, HLA-B27, is a strong risk factor for susceptibility to a group of disorders termed spondyloarthropathies. Rodents that express HLA-B27 develop spondyloarthropathies, implicating HLA-B27 in the etiology of these disorders. To determine whether an HLA-B27-like molecule was associated with spondyloarthropathies in nonhuman primates, we analyzed the MHC class I cDNAs expressed in a cohort of rhesus macaques that developed reactive arthritis after an outbreak of shigellosis. We identified several cDNAs with only limited sequence similarity to HLA-B27. Interestingly, one of these MHC molecules had a B pocket identical to that of HLA-B39. Pool sequencing of radiolabeled peptides bound by this molecule demonstrated that, like HLA-B27 and HLA-B39, it could bind peptides with arginine at the second position. However, extensive analysis of the MHC class I molecules in this cohort revealed no statistically significant association between any particular MHC class I allele and susceptibility to reactive arthritis. Furthermore, none of the rhesus MHC class I molecules bore a strong resemblance to HLA-B27, indicating that reactive arthritis can develop in this animal model in the absence of an HLA-B27-like molecule. Surprisingly, there was a statistically significant association between the rhesus macaque MHC A locus allele, Mamu-A*12, and the absence of reactive arthritis following Shigella infection.

Chemical modification of carboxyl groups in human fcγ fragment—II. Location of acidic residues involved in complement activation

Abstract The location of the acidic residues on human Fc γ 1 which are responsible for the loss of complement-activating capacity upon chemical modification has been established. As many as 13 residues get modified at the point of functional inactivation, of which only 6 are located in the C γ 2 region. Residues Glu (269) and Glu (318) are very reactive and may be extensively modified without significantly affecting anticomplementary capacity. Both Glu (333) and Asp (249) appear to be partially labelled. They are possibly involved in intramolecular ionic pairs (Deisenhofer, 1981), so that their contribution to complement activation is considered dubious. Extensive modification of Glu (258) and Glu (293) adds to the more rapid one of Glu (269) and Glu (318) resulting in abrogation of anticomplementary capacity. The data support the idea that a charge component may be an essential part of the mechanism of complement activation. They also help to define the nature of the Fc effector site that mediates this activity.

The effect of the chemical modification in human Fcγ fragment on protein A and Fc receptor binding

The role of acidic side-chains on Fc gamma fragment in granulocyte receptor binding and in S. aureus protein A binding has been investigated by means of chemical modification. Alteration of a restricted number of carboxyl groups after 5 min of reaction is sufficient to abrogate the capacity of Fc to inhibit EA rosette formation by human neutrophils. More limited modification, which affects mainly the most exposed acidic chains, does not change receptor binding activity. In contrast, the interaction with protein A is largely unaffected, even under reaction conditions which are able to induce significant changes in the circular dichroism spectrum of Fc fragment. The results suggest that some acidic groups on Fc may be involved in the interaction with neutrophil receptor and that the binding to protein A and Fc receptor involves different sites.