HLA AND SKIN DISORDERS
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This document discusses the role of HLA (human leukocyte antigen) genes in various skin diseases. It begins by describing HLA structure and function, noting that HLA genes encode antigen-presenting molecules and play a key role in the immune system. The document then examines associations between specific HLA alleles and a wide range of inflammatory, autoimmune, and infectious skin diseases. It also reviews how HLA type can influence susceptibility to drug eruptions and metabolic disorders. In conclusion, the author states that studying HLA associations with skin disease can provide insights into disease diagnosis, prognosis, clinical course, and potential new therapies.
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HLA AND SKIN DISORDERS
- 1. HLA AND SKIN DISEASES Dr.Rohit Kumar Singh Resident ,MD Dermatology Base Hospital ,LKO
- 2. CONTENTS Introduction HLA structure and function HLA and disease association Inflammatory disease Autoimmune disease Infections Drugs Metabolic diseases Conclusion Referrences
- 3. INTRODUCTION Major Histocompatibility Complex 1. Cluster of genes found in all mammals 2. Its products play role in discriminating self/non-self 3. Participant in both humoral and cell-mediated immunity MHC Act As Antigen Presenting Structures. In Human MHC Is Found On Chromosome 6.
- 4. CONT…. Two groupes of MHC genes: structurally and functionally distinct class I recognition by CD8+ T cells class II recognition by CD4+ T cells HLA molecules are responsible for the compatibility of the tissues of genetically different individuals and for the rejection of transplant
- 5. CONT…. MHC genes are codominantly expressed in each individual . Monozygotic twins have the same histocompatibility molecules on their cells. MHC genes are the most polymorphic genes present in the genome! (Up to 250 alleles identified for some loci)
- 6. HLA STRUCTURE MHC CLASS I Region B C D Gene product HLA - B HLA- C HLA - D Minor genes include E ,F ,G
- 7. HLA CLASS I STRUCTURE 1. Heavy chain α1, α2 domain: polymorphic sites α3 domain: binding of CD8 2. β-2 microglobulin 3. Peptide HETERODIMER PROTEIN
- 8. HLA STRUCTURE Region DP DQ DR Gene DP DQ DR product αβ αβ αβ MHC CLASS II Other minor MHC class protein includes DM ,DO
- 9. HLA CLASS II STRUCTURE 1. α chain α1: polymorphic sites α2: binding of CD4 2. β chain β1: polymorphic sites β2: binding of CD4 3. Peptide HETERODIMER PROTEIN
- 10. HLA STRUCTURE MHC CLASS III Region C4 C2 BF Gene product ‘C’ PROTEINS TNF –α, TNF-β
- 11. B lymfocyte CD4 T lymfocyte HLA class I. antigen TCR CD8 T lymfocyte APC ER, Golgi HLA class II. antigen TCR CD4 T lymfocyte APC lysozome ER, Golgi HLA class II. antigen TCR Endogenous Exogenous B lymfocytes Cell destruction immune response antibody production
- 12. HLA AND DISEASE ASSOCIATIONS 1. Molecular mimicry 2. Unbalanced binding among histocompatibility molecules and other MHC genes 3. HLA molecules – receptors for disease causing agents 4. Viral or bacterial antigens acts as superantigens 5. Induced expression of class II HLA Ag in tissue cells that normally do not perform it.
- 13. Disease HLA Relative risk Ankylosing spondyloarthritis B27 87.4 Uveitis B27 10 Goodpasture syndrome DR2 15.9 Multiple sclerosis DR2 4.8 Graves-Basedow DR3 3.7 disease Systemic lupus erythematosus DR3 5.8 Myasthenia gravis DR3 2.5 Pemphigus DR4 14.4 Rheumatoid arthritis DR4 4.2 Hashimoto thyroiditis DR5 3.2
- 14. Broadly grouped into three 1. Inflammatory diseases 2. Inherited errors of metabolism- 21- hydroxylase def. (HLA –BW47). 3. Autoimmune diseases(mainly with alleles at DR locus).
- 16. Includes all post –infectious arthropathies, all associated with HLA – B27(seronegative spondyloarthritis) Includes 1. Ankylosing spondylosis 2. Reiter’s disease 3. Acute anterior uveitis 4. Inflammatory bowel disease 5. Psoriatic arthritis
- 17. ATOPIC DERMATITIS • Chronic inflammatory HLA – A 24 • Most important • Increase IgE levels HLA – A 33 ,-B44,- DR13, -Bw6,-DR53,-DR4 • Other associations disease • Recurrent and highly pruritic disease • Allergic rhinitis and Asthma
- 19. LUPUS ERYTHROMATOSUS • Autoimmune disorder • SCLE and DLE affect skin HLA – B 8 HLA – DR 3 • SCLE HLA – DR 3 • Neonatal lupus erythromatosus HLA – A1 , -B8 ,- DR 3 , -B7 , -DR 2 • DLE HLA –DR 2 HLA –DR 3 • SLE
- 20. SYSTEMIC SCLEROSIS/SCLERODERMA Autoantibodies Clinical features HLA association Anticentromere CREST synd.(limited skin disease) HLA-DQ5,-DQ7,- DQ4 Anti-Topoisomerase I (scl – 70) Diffuse disease (Pulmonary ds) HLA-DQ7 HLA-DR5,-DR2,- DR7 Anti – PM -scl Overlap with myositis HLA-DR3,-DQ2 Anti –U1RNF Overlap with myositis HLA-DR4 Anti –U3RNF Diffuse skin ds. HLA – DRB1*1302
- 21. PSORIASIS HLA-B13,- Bw57,-Cw6,- DR7 • Early onset(<40) HLA-A2,-B27 • Late onset HLA-Cw6 • Aggravation( infection. Of strept) HLA-B13,-B17 • Guttate ,erythrodermic psoriais HLA-Cw6,-B13, -B16,-B17 • Psoriasis ± arthropathy HLA-B27,-B7,- B38,-B39 • Psoriatic Arthropathy
- 22. PSORIASIS HLA-B27 • Pustular psoriasis • Acrodermatitis of hallopeau • Spinal involvement HLA-B38,-B39 • Peripheral polyarthrithis HLA-DR4 • Rheumatoid type of arthropathy HLA-Aw19, -Bw35 • Pustulosis of palm and soles HLA-B39,-B27, -DQw3 • Disease progression in early psoriatic arthropathy
- 23. BULLOUS DISORDERS Disease Autoantibodies HLA-associations Pemphigus vulagaris Dg III HLA-DR4,-DR6, -DQ8,-DR14 Pemphigus folacious Dg I HLA-DR1,-DR4, -DR14 Epidermolysis bullosa acquisita Collagen type VII HLA-DR2 Dermatitis herpetiformis Unknown HLA-DQ2,-DQ8, -DR3,-DR7
- 24. VITILIGO Polygenic autoimmune disease HLA - DR 4 • Most important • Early age HLA - DR w 6 • Late age • Extensive lesions HLA – DR 7 • Acrofacial involvement HLA- DR w12, A-2, HLA – A 30,-cw6,DQw3 • Positive family history • Other associations
- 25. HLA ASSOCIATION WITH INFECTIONS
- 26. MYCOBACTERIAL HLA – DR2 ,-DR3 • Tuberculoid leprosy HLA – DQ1 • Lepromatous leprosy • Tuberculosis • Leprosy • Chronic inflammatory disease
- 27. CUTANEOUS LESMANIASIS HLA – A11, -B5,-B7 • Diffuse cutaneous leishmaniasis HLA – Bw22 HLA – DQ w3 • Localized cutaneous leishmaniasis HLA – DQw3 • Mucocutaneous leishmaniasis HLA –DQw3 = marker for Risk HLA – DR 2 = Protection
- 28. SCABIES HLA – A 11 • Increased Susceptibility • Resistant To Treatment • Multiple Nodular Lesions
- 29. HLA ANTIGENS ASSOCIATION WITH INFECTIONS Bacterial Ankylosing spondylitis HLA-B27 Reiter’s disease HLA-B27 Acute Anterior uveitis HLA-B27 Viral Dengue hemorrhagic fever HLA-DR15 HIV-1 HLA-DR13,-DR-2 Hepatitis -C HLA-A2, HLA-DR5 Hepatitis - B HLA-DR13 EBV HLA-B35.01,-A11,-B27 Parasite Malaria HLA-B53 Schistosomiasis HLA-DR3,-B5
- 30. HLA ASSOCIATIONS WITH DRUGS
- 31. DRUGS WITH HLA ASSOCIATIONS DRUG REACTION HLA- RELATED CARBAMAZEPINE SJS/TEN HLA-B *1502 ALLOPURINOL SJS/TEN HLA-B *5801 OXICAM SJS/TEN HLA – A2,-B12 ABACAVIR DRESS HLA-B*5701 AMINOPENICILLINS DRESS HLA-A2,-Drw52 ASPIRIN DRESS HLA-DRB1*1302 HLA-DQB1*6690 LAMOTRIGINE DRESS HLA- B*5801 COTRIMOXAZOLE FDE HLA-A30,-B13,-Cw6 NSAIDS NEPHRITIS HLA-DR FLUCLOXACILLIN LIVER TOXICITY HLA-B*5701 CO-AMOXICLAV LIVER TOXICITY HLA-DRB1*1501 DICLOFENAC LIVER TOXICITY HLA-DRB1*13
- 32. HLA ASSOCIATION WITH METABOLIC DISEASES
- 33. METABOLIC DISORDERS Diabetes mellitus HLA-DR2,-DR6,-DR11 Myasthenia Gravis HLA-B8,-DR3,-DR1 Rheumatoid arthritis HLA-DR1, -DR4, -DR5,-DR8,- DR12
- 34. CONCLUSION HLA association with skin disease is important to study as it can contribute to 1. Diagnosis 2. Prognosis 3. Characterization of type and clinical course 4. Anatomical predilection in certain dermatosis 5. Novel therapeutic treatments - like protease inhibitors designed to alter the antigen presenting property of the HLA.
- 35. REFERENCES 1. FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE 2. ROOK’S TEXTBOOK OF DERMATOLOGY 3. IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND AMEET VALIA 4. DERMATOLOGICAL SIGNS OF INTERNAL DISEASE BY JEAN L BOLOGNIA
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