Differential association of HLA DR genotypes with chronic, neurotoxin-mediated illnesses: Possible genetic basis for susceptibility?

Ritchie Shoemaker, Dennis House
Center for Research on Biotoxin-Associated Illness (a not-for-profit Corporation)
500 Market Street, Suite 102, Pocomoke City, MD 24851

The recently published paradigm of chronic biotoxin-induced illness involves multiple-system symptoms, a neurologic deficit as indicated by visual contrast sensitivity measurement, and symptom resolution concomitant with vision recovery following cholestyramine treatment to bind and eliminate toxins. Chronic illness can follow exposure to toxins from Ciguatera, Pfiesteria and other dinoflagellates (dinoflagellate-related illness, DRI), Aspergillis, Penicillium, Stachybotrys and other indoor air fungi (sick building syndrome, SBS), nasal resident coagulase negative Staphylococcus (CNS), and bacteria and protozoa associated with Post-Lyme Syndrome (PLS). Because some exposed individuals acquire only acute illness or are unaffected, we suspected that susceptibility to chronic illness was conferred by particular patterns of genetic polymorphisms, perhaps those coding for antigen presentation to immune T cells. Alleles at five loci on the class II human leukocyte antigen (HLA) genome were identified with commercial PCR analyses, 2 alleles for DRB1, DQ and DRB3, and 1 allele for DRB4 and DRB5, for 200 chronically ill patients with well established exposure potentials.

In each of the four patient classes, analyses identified unique and disproportionate patterns of HLA alleles within the patients' entire sets of alleles, relative to the entire patient population and to published frequencies in a large normal population. Statistically significant differences in allele fingerprints were: DRI - DRB1-4, DQ-8, DRB4-53; SBS - DRB1-7 or 17, DQ-2, DRB3-52A; CNS - DRB1-11, DQ-7, DRB3-52B; and PLS - DRB1-15, DQ-6, DRB5-51. The specific allele pattern was present in about 90% of patients in each class, and only about 5% of patients also showed an allele pattern associated with another patient class. The few patients with illness suspected to involve two types of exposure had allele patterns associated with risk from both types of exposure. In addition, several patients with histories of illness in more than one of the patient classes showed another allele pattern, DRB1-14, DQ-5 and DRB3-52B. Preliminary data indicated that the biotoxin exposure associated with each patient class and allele pattern may also be associated with a distinct pattern of elevation in proinflammatory cytokines.

These preliminary results suggest that distinct genetic patterns may be risk factors for chronic illness from exposure to particular classes of biotoxins. Susceptibility may involve cloaked or inappropriate presentation of antigens to T cells, and ensuing ineffective antibody production. A larger patient-population study that includes a prospective component is needed to confirm the possibility that particular HLA genotypes are risk factors for acquisition of chronic, neurotoxin-mediated illness, and to investigate the possible roles of proinflammatory cytokines in the toxic modes of action. Chronic inflammation is a known risk factor for development of a variety of diseases.