Previous association studies have shown a link of polymorphism of MICA/B and/or alteration in sMICA/B to cancers, autoimmunity and host-graft reaction[11, 17, 19, 25, 26, 34–36]. Serum sMICA/B levels are potential biomarkers of pathogenic implications for these disease conditions. For instance, upregulation of sMICA/B may be involved in the escape of tumor cells from immune cell attack and clearance[1–3, 19, 26, 27]. Accordingly, inhibition of sMICA/B production and/or preventing their shedding from cell surface may be of therapeutic potential in treating these human diseases[24, 37]. A better understanding of sMICA/B alteration in a broad disease spectrum is of important clinical relevance. Using a relatively large sample pool, we show here elevations of serum sMICA in association with infectious diseases in addition to cancers in a southern Chinese Han population.
Elevations of serum sMICA and sMICB have been shown in a number of malignant diseases, with sMICA potentially being more suitable than sMICB for early diagnosis of some cancers[33, 34]. Specifically, lung, breast, digestive system (hepatic, pancreas, gastric, colorectal) and urological cancers (prostate and renal) are associated with significant increase of serum sMICA relative to healthy controls as well as benign tumors. Consistent with these reports, the present study finds elevation of serum sMICA among Chinese patients with several types of malignant tumors, which are, or are approaching to, statistical significance relative to controls. In particular, the elevation appears to be especially dramatic in the hepatic cancer patients. The present data also suggest a certain extent of correlation of sMICA levels to the clinical stages of hepatic cancer. Thus, a significant difference exists between T2, T3 and T4 as compared to T1 stage cases, as well as between T2 and T3 stage patients. Somewhat surprising, the levels of sMICA are reduced in T4 compared with T3 stage patients in our studied cohort. One possible explanation for this finding may be that the lowering of sMICA in the T4 stage group occurs as a result of severe systematic or hepatic deficiency in cell function, such as failure of protein synthesis, among end-stage cancer patients. The ROC analysis in the present study reveals moderate diagnostic value for liver cancer, but marginal impacts for other cancer types. Taken together, serum sMICA and ROC analyses in the present study suggest a trend of elevation of the protein in liver, lung and laryngeal carcinomas in Chinese population, with the laboratory test being of significant value in the diagnosis and prognosis of hepatic cancer.
Evidence suggests that infections by microbiological pathogens may alter the expression and functionality of membrane bound MICA/B[2, 4, 16, 36]. For instances, changes in MICA/B and/or NKG2D levels and their activities are associated with infections caused by human cytomegalovirus, hepatitis B and C viruses[14, 29], herpes simplex virus, human immunodeficiency virus and vesicular stomatitis virus. Sex-transmitted Chlamydia trachomatis may also down-regulate MICA/B expression on cell membrane[16, 44, 50]. However, whether infections caused by microbiological pathogens also affect serum sMICA levels remains poorly understood.
The present study provides evidence that serum sMICA levels are elevated in various infectious diseases by microbiological pathogens. In detail, sMICA levels are increased to above 2 fold in bacterial infections with enterobacteriaceae, mycobacterium tuberculosis, Gram-positive cocci, non-fermenting Gram-negative bacteria and Microspironema pallidum. Among virus infectious diseases, sMICA levels are significantly increased in hepatitis B and C. However, we fail to find significant elevations of sMICA among patients infected by herpes simplex virus, Coxsackie virus, Epstein-Barr virus, cytomegalovirus, hepatitis A virus and hepatitis E virus, and by the Canidia albicans fungus. These data implicate that increased shedding of membrane MICA molecules presumably from infected/inflammatory cells may occur in several types of infectious diseases, which may lead to the observed rise of sMICA in serum. Given the findings of the elevation in many but not all infectious diseases, one may hypothesize that the extent of sMICA elevation could be potentially relevant to either the pathogens, or alternatively, the amount of involvement of infected cells in the body. Our ROC analyses suggest that serum sMICA measurement appears to have an intermediate diagnostic value for infections with hepatitis B and C virus, Microspironema pallidum, tuberculosis and Gram-negative bacteria (i.e., AUC > 0.7).