SEQUENCE VARIABILITY ANALYSIS OF HLA MOLECULES
(antigen presenting platform)

        Classical major histocompatibility complex (MHC) molecules play a key role in the immune system by capturing peptide antigens and presenting them for recognition by T cell receptors (TCRs). There are two major classes of MHC molecules, class I and class II. MHC class I (MHCI) molecules are expressed on most cells, bind endogenously derived peptides, and are recognized by CD8 cytotoxic T lymphocytes (CTL). On the other hand, MHC class II (MHCII) molecules are present only on professional antigen-presenting cells (APC), bind exogenously derived peptides, and are recognized by CD4 helper T-cells (Reinherz, and Schlossman, 1980; Stern and Wiley, 1994; Madden, 1995; Garcia et al., 1999).

       In the human, MHC molecules are referred to as HLA, an acronym for human leukocyte antigens (HLA). The classical HLA class I (HLA I) molecules are of three types, HLA-A, HLA-B and HLA-C. Likewise, the classical HLA class II (HLA II) molecules are also of three types (HLA-DP, HLA-DQ and HLA-DR). Genes encoding classical HLA molecules are extremely polymorphic. Thus, the HLA IMGT/HLA Database currently includes 1524 HLA allelic sequences (904 HLA I alleles and 620 HLA II alleles) (Release 1.16, 14/10/2002). Allelic variation among the classical HLA varies for the different gene subtypes, and is the basis for differential peptide binding, thymic repertoire bias and allograft rejection. Hence, identification of HLA polymorphisms has relevant functional implications. Thus, we have recently revised the sequence variability of HLA molecules using the Shannon entropy equation (Shannon, 1948; Schneider, 1997) as our variability meassure (V), and identified that most polymorphisms (defined as sites with V > 1) consist of peptide binding residues at the a1a2 and a1b1 domains of HLA I and II molecules, respectively. Nevertheless, some polymorphisms were also identified in positions that were involved in TCR binding.

       This analysis of the sequence variability of HLA molecules is the basis of a manuscript by Reche and Reinherz (2003) which is now under revision. Here we show the sequence alignments of the antigen presenting platform of HLA I and II molecules ( a1a2 and a1b1 domains, respectively) from which the variability analyses were performed. Mapping of HLA sequence variability onto their relevant 3D structures is also available for visualization from this server.

Sequence variability analysis using the Shannon entropy meassure can be perfomed from any custom multiple sequence alignment at our Sequence Variability Server.

Mapping sequence variability within a multiple sequence alignment onto a relevant 3D structure is also available at our entropy2pdb web server.

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Stern, L. J. & Wiley, D. C. (1994).. Antigen peptide binding by class I and class II histocompatibility proteins. Structure 2, 245-251
Madden, D. R. (1995). The three-dimensional structure of peptide-MHC complexes. Annu. Rev. Immunol. 13, 587-622.
Schneider, T. D. (1997). Information content of individual genetic sequences. J Theor Biol 189, 427-441.
Garcia, K. C., Teyton, L. & Wilson, I. A. (1999). Structural basis of T cell recognition. Annu Rev Immunol 17, 369-397.
Reche P.A. & Reinherz E.L. (2003). Co-evolution of allelic variability in HLA polymorphism and T cell receptor-based immunorecognition (Submmited)