HLA-DR Haplotypes & CIRS Susceptibility: Research

93 papers · Curated by Lauren Lowenstein, The Biotoxin Lady

Ever wondered why you're the one who got sick when everyone else in the house seems "fine"? Genetics is a big part of the answer.

HLA-DR genes help your immune system present foreign material, like biotoxins, so it can be tagged and cleared. Certain HLA-DR haplotypes appear to make that harder. In the Shoemaker framework, people with these "susceptible" patterns may not clear biotoxins efficiently after exposure, so the immune system stays stuck in an inflammatory state instead of shutting off. Some haplotypes are linked to mold, some to Lyme, and some, called multisusceptible (like 4-3-53 and 4-7-53), to many biotoxin sources. Others are associated with low MSH.

When our family got our results, so much finally made sense. My kids included.

The important part: a haplotype is not a diagnosis, and it's not a life sentence. It doesn't mean you'll develop CIRS. It helps explain risk and why recovery can stall. People with even the "dreaded" haplotypes still respond well to treatment with the right support.

This hub collects about 93 research papers on HLA-DR genetics and biotoxin susceptibility: Shoemaker's original haplotype work, HLA associations in related inflammatory conditions, and newer immunogenetics research.

Look up what each haplotype means in my HLA-DR haplotypes guide, or plug in your lab results with the free HLA calculator.

Educational only, not medical advice.

— Lauren Lowenstein, The Biotoxin Lady · Last reviewed October 19, 2026

Key facts

  • HLA-DR genes help the immune system recognize and present antigens, including biotoxins.
  • Certain haplotypes are linked to susceptibility to mold, Lyme, or multiple biotoxins, and some to low MSH.
  • A susceptible haplotype explains risk. It isn't a diagnosis of CIRS.
  • Testing is a simple blood test, and results are read with a haplotype chart or calculator.

Key research papers

  1. Sick building syndrome (SBS) and exposure to water-damaged buildings: Time series study, clinical trial and mechanisms

    Ritchie C. Shoemaker et al. · Neurotoxicology and Teratology · 2006

  2. HLA-DRB1*1501, -DQB1*0301, - DQB1*0302, -DQB1*0602, and DQB1*0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis

    Zivadinov R et al. · International review of neurobiology · 2007

  3. Characterization of Airborne Molds, Endotoxins, and Glucans in Homes in New Orleans after Hurricanes Katrina and Rita

    Rao CY et al. · Applied and Environmental Microbiology · 2007

  4. Immunogenetics of atopic asthma: association of DRB1*1101 DQA1*0501 DQB1*0301 haplotype with Dermatophagoides spp.‐sensitive asthma in a sample of the Venezuelan population

    Lara-Marquez ML et al. · Clinical & Experimental Allergy · 1999

  5. HLA-DRB1 alleles and HLA-DRB1 shared epitopes are markers for juvenile rheumatoid arthritis subgroups in Colombian mestizos

    Garavito G et al. · Human Immunology · 2004

  6. Sick building syndrome in water-damaged buildings: generalization of the chronic, biotoxin-associated illness paradigm to indoor toxigenic fungi

    Ritchie C. Shoemaker et al. · Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health · 2005

  7. The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

    Newton J et al. · Arthritis & Rheumatism · 2003

  8. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis

    Albert J. Czaja et al. · Immunological Reviews · 2000

  9. A three-way interplay of DR4, autoantibodies and synovitis in biopsy-proven idiopathic inflammatory myositis

    Limaye VS et al. · Rheumatology International · 2012

  10. HLA-DQA, -DQB and –DRB allele contribution to narcolepsy susceptibility

    Planelles D et al. · European Journal of Immunogenetics · 1997

  11. Nationwide collaborative study of HLA class II associations with distinct types of juvenile chronic arthritis (JCA) in Greece

    Pratsidou-Gertsi P et al. · European Journal of Immunogenetics · 1999

  12. HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis

    Toussirot E et al. · The Journal of Rheumatology · 1999

  13. Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401

    Coakley G et al. · British journal of rheumatology · 2000

  14. HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies

    O’Hanlon T et al. · Arthritis & Rheumatism · 2006

  15. Sequential upregulation of innate immune responses during acute acquisition of illness in patients exposed prospectively to water-damaged buildings. ASTMH, Philadelphia, PA

  16. Innate immunity, MR spectroscopy, HLA DR, TGF beta-1, VIP and capillary hypoperfusion define acute and chronic human illness acquired following exposure to water-damaged buildings. 2008. International Healthy Buildings (conference peer review)

    Ritchie C. Shoemaker et al. · 2008

  17. Correction of central nervous system metabolic abnormalities, deficits in executive cognitive functioning and elevated C4a: a clinical trial using low dose erythropoietin in patients sickened by exposure to water-damaged buildings. IACFS, Fort Lauderdale, Florida

  18. Redefining the HLA and RA association: to be or not to be anti-CCP positive

    de Vries RR et al. · Journal of Autoimmunity · 2005

  19. Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis

    Gonzalez-Gay MA et al. · Seminars in Arthritis and Rheumatism · 2002

  20. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

    van Gaalen FA et al. · Arthritis & Rheumatism · 2004

  21. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

    Agarwal K et al. · Hepatology · 2000

  22. Hla antigens in juvenile Arthritis

    Fernandez-Vina MA et al. · Arthritis & Rheumatism · 1990

  23. HLA-DRB1, DQA1, and DQB1 genotypes in patients with nasal polyposis

    Molnar-Gabor E et al. · The Laryngoscope · 2000

  24. HLA-DRB1 and -DQB1 loci in three west African ethnic groups: Genetic relationship with sub-Saharan African and European populations

    Lulli P et al. · Human Immunology · 2009

  25. HLA-DRB1 allele distribution in polymyalgia rheumatica and giant cell arteritis: influence on clinical subgroups and prognosis

    Martínez-Taboda VM et al. · Seminars in Arthritis and Rheumatism · 2004

  26. A new categorization of HLA DR alleles on a functional basis

    Ou D et al. · Human Immunology · 1998

  27. Association of HLA‐DQA1∗03011‐DQB1∗0301 haplotype with the development of respiratory scleroma

    Sanchez-Marin L et al. · Otolaryngology · 2007

  28. HLA DRB1*1501 and intrathecal inflammation in multiple sclerosis

    Sellebjerg F et al. · Tissue Antigens · 2000

  29. Confirmation of the novel association at the BTNL2 locus with ulcerative colitis

    Pathan S et al. · Tissue Antigens · 2009

  30. Autoimmune hepatitis

    Vergani D et al. · Minerva Gastroenterol Dietol · 2004

  31. Generic human leukocyte antigen class II (DRB1 and DQB1) alleles in patients with paracoccidioidomycosis

    Sadahiro A et al. · Medical Mycology · 2007

  32. HLA class II alleles and genetic predisposition to the antiphospholipid syndrome

    Domenico Sebastiani G et al. · Autoimmunity Reviews · 2003

  33. Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

    Mamyrova G et al. · Arthritis & Rheumatism · 2006

  34. HLA-DRB1 alleles may influence disease phenotype in patients with inflammatory bowel disease: a critical reappraisal with review of the literature

    Vito Annese et al. · Diseases of the Colon & Rectum · 2004

  35. Molecular Analysis of HLA Class ll-Associated Susceptibility to Neuroinflammatory Diseases in Korean Children

    Oh HH et al. · Journal of Korean Medical Science · 2004

  36. ACCESS Group HLA and environmental interactions in sarcoidosis

    Rossman M et al. · Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG · 2008

  37. DNA analysis of HLA-DR, DQ, and DP, Alleles in children with polyarticular juvenile rheumatoid arthritis

    Barron KS et al. · The Journal of Rheumatology · 1992

  38. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis

    Brucklacher-Waldert V et al. · Brain · 2009

  39. Borrelia burgdorferiInduces TLR1 and TLR2 in Human Microglia and Peripheral Blood Monocytes but Differentially Regulates HLA-Class II Expression

    Ingoni R et al. · Journal of Neuropathology & Experimental Neurology · 2006

  40. The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis

    Chauhan B et al. · The Journal of Immunology · 1997

  41. Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis

    Ferucci ED et al. · Arthritis & Rheumatism · 2005

  42. Complex genetic predisposition in adult and juvenile rheumatoid arthritis

    Miterski B et al. · BMC Genetics · 2004

  43. Human leukocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis

    Melin-Aldana H et al. · The Journal of Pediatrics · 1992

  44. Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-dr in monocytes during septic shock

    Fumeaux T et al. · American Journal of Respiratory and Critical Care Medicine · 2002

  45. Novel function of complement C3d as an autologous helper T-cell target

    Knopf P et al. · Immunology and Cell Biology · 2008

  46. HLA DRB1*1501 is only modestly associated with lesion burden at the first demyelinating event

    Horakova D et al. · Journal of Neuroimmunology · 2011

  47. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles

    Steere AC et al. · The Pediatric Infectious Disease Journal · 1990

  48. Expression of triggering receptor on myeloid cell 1 and histocompatibility complex molecules in sepsis and major abdominal surgery

    Nestor González-Roldán · World Journal of Gastroenterology · 2005

  49. Expression of QK/QR/RRRAA or DERAA motifs at the third hypervariable region of HLA-DRB1 and disease severity in rheumatoid arthritis

    Khani-Hanjani A et al. · The Journal of Rheumatology · 2002

  50. How regulatory T cells work

    Shen L et al. · Nature reviews. Immunology · 2009

  51. α-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases

    Brozska T et al. · Endocrine Reviews · 2008

  52. The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10

    de Kleer IM et al. · Arthritis & Rheumatism · 2003

  53. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia

    Walker C et al. · American Journal of Respiratory and Critical Care Medicine · 1994

  54. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi

    Kalish RA et al. · Infection and Immunity · 1993

  55. In vitro effects of trichothecenes on human dendritic cells

    Hymery N. Sibiril Y et al. · Toxicology in Vitro · 2006

  56. CD4+CD25bright Regulatory T Cells Actively Regulate Inflammation in the Joints of Patients with the Remitting Form of Juvenile Idiopathic Arthritis

    de Kleer IM et al. · The Journal of Immunology · 2004

  57. Reproducibility of Immunological Tests Used To Assess Multiple Chemical Sensitivity Syndrome

    Hoover DR et al. · Clinical and Vaccine Immunology · 2003

  58. Early and late antibody responses to full-length and truncated constructs of outer surface protein A of Borrelia burgdorferi in Lyme disease

    Kalish RA et al. · Infection and Immunity · 1995

  59. Harmful molecular mechanisms in sepsis

    Daniel Rittirsch et al. · Nature reviews. Immunology · 2008

  60. Fibrotic Mechanisms in Idiopathic Rapidly Progressive Glomerulonephritis: The Role of TGF-β1 and C5b-9

    Gionanlis L et al. · Renal Failure · 2008

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