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Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross-reactions.

Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of refined wheat products that lack zinc and other critical nutrients as a consequence of the refining process. On the other hand, plasma zinc concentration is influenced by proinflammatory cytokines (IL-6 and TNF-alpha) and by metallothioneins (MT) homeostasis, which is in turn affected by proinflammatory cytokines. MT increase in aging and chronic inflammation allowing a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon leads to an impaired inflammatory/immune response in the elderly. A major target of zinc is NF-kappaB, a transcription factor critical for the expression of proinflammatory cytokines whose production is regulated by extra- and intracellular activating and inhibiting factors interacting with the regulatory elements on cytokine genes. Effects of zinc on translocation of NF-kappaB have been attributed to the suppression of phosphorylation and degradation of the inhibitory proteins (A20) that normally sequester it in the cytoplasm. Moreover, this factor and A20 are regulated by specific genes involved in inflammation and by intracellular zinc ion availability. So, it is not so surprising that zinc deficiency is constantly observed in chronic inflammation, such as in old individuals. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms are associated with atherosclerosis and diabetes type 2. Therefore, zinc turnover, via MT homeostasis, in individuals genetically predisposed to a dysregulation of the inflammatory/immune response may play a crucial role in causing possible adverse events with the appearance of age-related diseases.

In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunctions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases. It has been proposed that a small number of genes within the 8.1 AH modify immune responsiveness and hence affect multiple immunopathological diseases. In this article, we demonstrate that neutrophil chemotaxis is significantly decreased in carriers of this AH, suggesting that this impairment may also be related to the increased occurrence of autoimmune diseases in these individuals.