Immunogenetic markers in immune mediated diseases

The aim of this thesis was to study HLA class II markers, as well as other - MHC and non MHC genes in different immune - mediated diseases, namely, cervical intraepithelial neoplasia (CIN), cervical cancer, juvenile idiopathic arthritis (JIA), mixed connective tissue disease (MCTD) and type I diabetes mellitus (T1 DM).

HLA class II genes are located on the short arm of chromosome 6 and are known to be important for pathogenesis of immune-mediated diseases due to the function of the molecules these genes encode. The HLA molecules present self and foreign peptides to the T cells thus playing major role in activation of pathogenetically important cells.

MICA gene in the MHC class I encodes for molecules that are ligands for NKG2D receptor on NK, (gamma)(delta)T cells, CD8+ T cells, CD28 negative (alpha)(beta)T cells and macrophages. Engagement of NKG2D by MICA leads to activation of the cells bearing this receptor. It has been shown that polymorphisms of the gene sequence can generate molecules with different affinities for NKG2D receptor and thus modulate the strength of activating signal.

TNF is a cluster of genes and microsatellites in the MHC class III. Many studies have reported associations of polymorphisms in this region with TNFalpha production. Furthermore, the microsatellites in this region are sometimes used as additional markers for association.

KIR genes encode for inhibitory and activating receptors expressed on NK cells and some subset of T cells. These receptors interact with classical HLA class I molecules and depending on the interaction can either inhibit or stimulate KIR bearing cells.

Our studies on cervical lesions showed that TNFa microsatellite polymorphisms in CIN and cervical cancer could not be considered as single markers for either CIN or cervical cancer. However, as a part of extended MHC haplotypes, these polymorphisms can contribute to susceptibility to infection with HPV virus. HLA DR15-DQ6 is the most attributable locus for development of HPV induced cervical lesions. We did not find any association of MICA microsatellite polymorphism with either CIN or cervical cancer.

The study of MICA and TNFa polymorphisms in JIA showed that MICA4 and TNFa2 are significantly positively associated with the disease in patients group. TNFa7 is significantly negatively associated with JIA. This suggests that MICA as well as TNFa genetically contribute to the disease pathogenesis, protection and susceptibility.

Our association study of the markers in HLA loci in Swedish MCTD patients demonstrated that susceptibility to MCTD may be linked to the MICA allele 5.1 and 4, and HLA-DRB1*04, and that all these markers in combination are necessary to confer increased genetic risk for MCTD.

The study of MICA gene microsatellite polymorphism in HBDI families revealed that allele 5.1 of this polymorphism was transmitted more frequently from healthy parents to affected offspring. This allele was transmitted more frequently together with high-risk HLA genes than alone. MICA 6 was transmitted less frequently.

The study on KIR genes in T1DM showed some genes associated with the disease. KIR 2DL2 and 2DS2 showed the strongest association. We found also that two specific genotypes were either positively or negatively associated with the disease. These two genotypes differed only by presence of 2DL2 in the genotype found more frequently in patients.

The conclusion we can draw from this study is that KIR genes are probably important in T1DM, although the functional importance of the cells bearing these receptors, as well as expression of these genes in subsets of cells important in pathogenesis of T1DM has to be ruled out still.

List of scientific papers

I. Ghaderi M, Nikitina L, Peacock CS, Hjelmstrom P, Hallmans G, Wiklund F, Lenner P, Blackwell JM, Dillner J, Sanjeevi CB (2000). Tumor necrosis factor a-11 and DR15-DQ6 (B*0602) haplotype increase the risk for cervical intraepithelial neoplasia in human papillomavirus 16 seropositive women in Northern Sweden. Cancer Epidemiol Biomarkers Prev. 9(10): 1067-70.
https://pubmed.ncbi.nlm.nih.gov/11045789

II. Ghaderi M, Nikitina Zake L, Wallin K, Wiklund F, Hallmans G, Lenner P, Dillner J, Sanjeevi CB (2001). Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer. Hum Immunol. 62(10): 1153-8.
https://pubmed.ncbi.nlm.nih.gov/11600224

III. Nikitina Zake L, Cimdina I, Rumba I, Dabadghao P, Sanjeevi CB (2002). Major histocompatibility complex class I chain related (MIC) A gene, TNFa microsatellite alleles and TNFB alleles in juvenile idiopathic arthritis patients from Latvia. Hum Immunol. 63(5): 418-23.
https://pubmed.ncbi.nlm.nih.gov/11975986

IV. Hassan AB, Nikitina-Zake L, Padyukov L, Karlsson G, Gupta M, Lundberg IE, Sanjeevi CB (2003). MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients. Hum Immunol. 64(2): 290-6.
https://pubmed.ncbi.nlm.nih.gov/12559632

V. Nikitina Zake L, Ghaderi M, Veys K, Park YS, Babu S, Eisenbarth G, Sanjeevi CB (2003). MICA gene polymorphism in HBDI multiplex families. [Manuscript]

VI. Nikitina Zake L, Ghaderi M, Rajalingam R, Brameus A, Rumba I, Sanjeevi CB (2003). Killer-cell immunoglobulin-like receptor genes in Latvian patients with type 1 diabetes mellitus and healthy controls. [Manuscript]