Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease.

The incidence of autoimmune diseases is increasing. Antinuclear antibody (ANA) testing is a critical tool for their diagnosis. However, ANA prevalence in healthy persons has increased over the last decades, especially among young people. ANA in health occurs in low concentrations, with a prevalence up to 50% in some populations, which demands a cutoff revision. This review deals with the origin and probable physiological or compensatory function of ANA in health, according to the concept of immunological clearance, theory of autoimmune regulation of cell functions, and the concept of functional autoantibodies. Considering ANA titers ≤1:320 as a serological marker of autoimmune diseases seems inappropriate. The role of anti-DFS70/LEDGFp75 autoantibodies is highlighted as a possible anti-risk biomarker for autoimmune rheumatic disorders. ANA prevalence in health is different in various regions due to several underlying causes discussed in the review, all influencing additive combinations according to the concept of the mosaic of autoimmunity. Not only are titers, but also HEp-2 IFA) staining patterns, such as AC-2, important. Accepting autoantibodies as a kind of bioregulator, not only the upper, but also the lower borders of their normal range should be determined; not only their excess, but also a lack of them or "autoimmunodeficiency" could be the reason for disorders.

Pathogenesis of Autoimmune Male Infertility: Juxtacrine, Paracrine, and Endocrine Dysregulation.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility is often associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, and thus preventing ovum fertilization. Infertility diagnosis requires a mandatory check for the ASAs. The concept of the blood-testis barrier is currently re-formulated, with an emphasis on informational paracrine and juxtacrine effects, rather than simple anatomical separation. The etiology of male infertility includes both autoimmune and non-autoimmune diseases but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter the blood-testis barrier, facilitating ASAs production as well. There are contradictory data on the role of ASAs in the pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to "danger concept" mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism, and hypothyroidism also facilitate ASAs production. The diagnostic value of various ASAs has not yet been clearly attributed, and their cut-levels have not been determined in sera nor in ejaculate. The assessment of the autoimmunity role in the pathogenesis of male infertility is ambiguous, so the purpose of this review is to show the effects of ASAs on the pathogenesis of male infertility.

Lymphopenia-induced proliferation of CD4 T-cells is associated with CD4 T-lymphocyte exhaustion in treated HIV-infected patients.

Background & objectives: Under the lymphopenic condition, T-cells divide to maintain their peripheral pool size. Profound chronic lymphopenia in some treated HIV-infected patients, characterized by poor T-cell recovery, might result in intensive homeostatic proliferation and can cause T-cell exhaustion and/or senescence. The present study was undertaken to evaluate the homeostatic proliferation of CD4+T-cells in treated HIV-infected individuals, and to determine the amount of phenotypically exhausted and senescent CD4 T-lymphocytes. Methods: Thirty seven treated HIV-infected patients with suppressed HIV viral load (<50 copies/ml) were studied. Patients were divided into two groups: immunological non-responders (INRs) with CD4+T-cells <350/µl (n=16) and immunological responders (IRs) with CD4+T-cells >350/µl (n=21). T-cell subsets [naïve, central memory (CM), and effector memory (EM)] and proportions of cycling (Ki-67+), senescent (CD57+) and exhausted (PD-1+) T-lymphocytes were assessed using flow cytometry. Results: CD4+T-cell cycling rate was higher in INRs than in IRs due to more extensive proliferation of CM, 4.7 vs 2.7 per cent (P <0.01) and EM, 4.8 vs 3.2 per cent (P <0.05). The percentages of CD4+Ki-67+ CM and EM T-lymphocytes were inversely related to the CD4+T-cell counts in the appropriate subset, r=-0.584 (P <0.001) and r=-0.556, (P <0.001), respectively. Exhaustion [24.2 vs 16.7% (P <0.01)], but not senescence [7.1 vs 10.8% (P>0.05)] was more pronounced in the INR group than in the IR group. The frequency of CD4+Ki-67+ CM T-cells was related to the proportion of CD4+PD-1+ cells of the same subset, r=0.789 (P <0.001). The numbers of CD4+Ki-67+PD-1+ CM and EM T-cells were substantially higher in INRs than in IRs. Interpretation & conclusions: The present data indicated that intensive homeostatic proliferation contributed to the T-cell exhaustion in HIV-infection.

Influence of hepatitis C virus coinfection on CD4⁺ T cells of HIV-infected patients receiving HAART.

OBJECTIVE: The effects of hepatitis C virus (HCV) coinfection on immune homeostasis and immune restoration in treated HIV infection are not well understood. METHODS: We studied 79 HIV-infected patients who had been receiving HAART for more than 2 years and who had HIV viral load below 50 copies/ml. Four patient groups were studied: HIV/HCV, CD4⁺ cells above 350/µl; HIV/HCV, CD4 cells below 350/µl; HIV/HCV, CD4 cells above 350/µl; HIV/HCV, CD4⁺ cells below 350/µl. Controls comprised 20 healthy volunteers. Naive, central memory, effector memory, and terminal effector CD4⁺ T cells were enumerated. Naive CD4CD31 T cells were counted as recent thymic emigrants (RTEs). Activation state and ex-vivo apoptosis of CD4⁺ T cells, levels of liver enzymes, and aspartate aminotransferase-to-platelet ratio index were evaluated. RESULTS: CD4⁺ T-cell counts and the numbers of all circulating CD4 T-cell maturation subsets were diminished in HIV infection; CD4⁺ T-cell activation and apoptosis were increased in HIV infection, but none of these indices was affected by HCV coinfection. RTE numbers were diminished in HIV infection, were inversely related to age, and were increased in women and lower in HIV/HCV patients than in singly HIV-infected patients. In coinfected patients, RTE numbers were inversely related to levels of liver enzymes, but not to HCV viral load. CONCLUSION: Whereas we could find no relationship between HCV infection and most indices of CD4⁺ T-cell homeostasis or activation, CD4⁺ RTEs are diminished in the circulation of HCV coinfected persons and appear to be related to indices of ongoing hepatic damage or inflammation.