HLA and sarcoidosis: new pathogenetic insights.
Many theories have been presented to account for the immunological and epidemiological features of sarcoidosis; several lines of study support the prevailing opinion that an environmental agent, possibly microbial in origin, may cause sarcoidosis in a genetically predisposed host. Many polymorphic genes have been suggested to contribute to this genetic susceptibility: genes encoding angiotensin converting enzyme, vitamin D receptor, and interleukin-1, T-cell receptor genes, Gm and Km immunoglobulin genes and, most relevant, HLA genes (classical and non classical). There is also some evidence of an HLA-associated protection against sarcoidosis. The main action of disease-associated HLA molecules is to present specific antigenic peptides in such a way that the recognizing T-lymphocytes initiate an inflammatory response with peculiar pathological consequences. Other, so-called, non-classical HLA genes coding for proteins involved in antigen processing and presentation, namely TAP, LMP and DM, seem to contribute. Particular alleles of the tumor necrosis factor gene cluster (TNFA, LTA, LTB) are known to be associated with peculiar clinical forms of sarcoidosis. For instance, Löfgren's syndrome, which is an acute form of pulmonary sarcoidosis with frequent spontaneous remission, is marked by the TNFA*2, HLA-DR3 haplotype. How many HLA genes are involved is still unknown, but it is now clear that the HLA region is strongly implicated in the development of sarcoidosis. Probably, the future lies in isolating and sequencing the putative peptide bound to susceptible MHC molecules which, activating reactive T-cells, is responsible for disease initiation and/or exacerbation. However, the investigative approach should not be confined only to genomic sequences: the temporal and spatial expression of gene products, the post-transcriptional modification of the protein products will be fundamental in determining the basic functional context of developing sarcoidosis.
Martinetti
Miryam
M
Servizio di Immunoematologia e Transfusione e Centro di Immunologia dei Trapianti, IRCCS Policlinico S. Matteo, Pavia, Italy. m.martinetti@smatteo.pv.it
Luisetti
Maurizio
M
Cuccia
Mariaclara
M
D005805:Genes, MHC Class I / Q000502:physiology; D005802:Genes, MHC Class II / Q000502:physiology; D006680:HLA Antigens / Q000502:physiology*; D006801:Humans; D012507:Sarcoidosis / Q000209:etiology* / Q000378:metabolism*
D006680:HLA Antigens