Immunoprinting Excludes Many Potential Susceptibility Genes as Predisposing to Early Onset Pauciarticular Juvenile Chronic Arthritis Except Hla Class Ii and TNF

Abstract

DNA profiles (immunoprints) were generated for 120 patients suffering from early onset pauciarticular chronic arthritis (EOPA-JCA) and > 500 healthy controls utilizing highly polymorphic microsatellites in the vicinity of immunorelevant genes. Six T cell receptor (TCR) markers for the CD3D, TCRDVAJ, TEA, TCRBV6S1, BV6S3, BV6S7 and BV13S2 genes were analysed. Furthermore markers for the cell surface molecule CD40L, for cytokine genes (IL-1A, IL-2, IFN-alpha, FGF-alpha, TNF-alpha), the chromosomal region of the IRF2 and the cytokine receptor gene IL5RA were studied as well as two polymorphisms within the promotor region of the TNF-alpha gene. Coding region polymorphisms were evidenced indirectly by repeat length variation or they were predicted from the microsatellite distribution profiles and then confirmed by direct sequence analysis. Statistical evaluations were performed with respect to known predispositions, predominance of females (> 80%) and HLA-DR and -DQ haplotypes. Cell surface molecules (TCR, CD40L, IL5RA) as well as almost all cytokines (IL-1A, IFN alpha, FGFA, IRF2 region) were excluded as predisposing in our JCA panel. The TNF-alpha microsatellite alleles (GT)10-12 contribute considerably to manifestation of the disease, in HLA-DRB1*11(12) individuals (RR = 12.8). The TNF-alpha allele is not found in linkage disequilibrium with HLA-DRB1*11(12) and may be present on either chromosome 6. Thus, a novel susceptibility factor probably within the TNFA/TNFB gene region has been identified via linkage with the TNF-alpha microsatellite allele. Apparently complex compositions of the genetic background rather than single genes provide the precondition for manifestation of the autoimmune disease EOPA-JCA. Immunoprinting unravels the variability of the immunological genome via the semi-directed microsatellite approach efficiently.

Immunoprinting reveals different genetic bases for (auto)immune diseases

“…Increased RR could be excluded in > 150 patients based on the aforementioned genetic markers predisposing to RA. However, TNFu alleles (GT),o-,2 are found more often in the EOPA patients that type HLA-DR5' than in matched controls [32]. This fact is interesting because DR5, the EOPApredisposing HLA type, and the aforementioned microsatellite alleles appear not to be in linkage disequilibrium.…”

Modern genome research and DNA diagnostics in domestic animals in the light of classical breeding techniques

“…Knowledge about the gene loci potentially involved leads to an approach termed immunoprinting in which markers are combined from numerous different loci of the immune system [64]. Meanwhile, immunoprinting has been applied to identify genes involved in the development of human rheumatoid arthritis of adults [65] and juveniles [66] as well as multiple sclerosis (C. Epplen et al, in preparation).…”

“…Mapping of a QTL in livestock by the random marker gene approach has already been achieved [66]. A threegeneration pedigree was produced from a cross between European wild boars and Large White sows.…”

Psychological risk factors and early complications after bone marrow transplantation in adults

“…To prove a causal link between psychological and cytokine-mediated processes, further experiments must first demonstrate that different FIT parameters coexist with different responses to inflammatory stimuli. The possibilities that individuals who exhibit a life-long FIT 3/4 pattern might have a tendency toward immunologic dissonance, monocyte paralysis, or even a variant program for the control of their cytokine genes 50,51 are all testable. Such a biological model rests upon the assumptions that psychological factors can influence biochemical reactions, that the primary psychological data were not epiphenomena of a transient physical state, and that underlying organ pathology did not generate the psychodynamic responses.…”