hla and skin disorders
TRANSCRIPT
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HLA AND SKIN DISEASES
Dr.Rohit Kumar Singh
Resident ,MD Dermatology
Base Hospital ,LKO
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CONTENTS
Introduction
HLA structure and function
HLA and disease association
Inflammatory disease
Autoimmune disease
Infections
Drugs
Metabolic diseases
Conclusion
Referrences
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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.
INTRODUCTION
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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
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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)
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HLA STRUCTURE
Region B C D
Gene
product
HLA - B HLA- C HLA - D
MHC CLASS I
Minor genes include E ,F ,G
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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
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HLA STRUCTURE
Region DP DQ DR
Gene
product
DP
αβ
DQ
αβ
DR
αβ
MHC CLASS
II
Other minor MHC class protein includes DM
,DO
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HLA CLASS II STRUCTURE
1. α chainα1: polymorphic sites
α2: binding of CD4
2. β chainβ1: polymorphic sites
β2: binding of CD4
3. Peptide
HETERODIMER
PROTEIN
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HLA STRUCTURE
Region C4 C2 BF
Gene
product
‘C’ PROTEINS TNF –α,
TNF-β
MHC CLASS
III
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CD4
T lymfocyte
B lymfocyte
HLA class I.
antigen
TCR
CD8
T lymfocyte
APCER, Golgi
HLA class II.
antigen
TCR
CD4
T lymfocyte
APClysozome
ER, Golgi
HLA class II.
antigen
TCR
Endogenous Exogenous B lymfocytes
Cell destruction immune response antibody
production
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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.
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Disease HLA Relative risk
Ankylosing
spondyloarthritis B27 87.4
Uveitis B27 10
Goodpasture
syndromeDR2 15.9
Multiple sclerosis DR2 4.8
Graves-Basedow
diseaseDR3 3.7
Systemic lupus
erythematosusDR3 5.8
Myasthenia gravis DR3 2.5
Pemphigus DR4 14.4
Rheumatoid arthritis DR4 4.2
Hashimoto thyroiditis DR5 3.2
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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).
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INFLAMMATORY DISEASES
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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
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ATOPIC DERMATITIS
HLA – A 24 • Most important
• Increase IgE levels
HLA – A 33 ,-B44,-
DR13,
-Bw6,-DR53,-DR4
• Other associations
• Chronic inflammatory
disease
• Recurrent and highly pruritic
disease
• Allergic rhinitis and Asthma
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AUTOIMMUNE DISEASE
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LUPUS ERYTHROMATOSUS
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
• Autoimmune disorder
• SCLE and DLE affect skin
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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
(Fibrillarin)
Diffuse skin ds.
(cardiac and renal)
HLA – DRB1*1302
HLA-DQB1,-DQ8
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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
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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
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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
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VITILIGO
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
Polygenic autoimmune
disease
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HLA ASSOCIATION WITH INFECTIONS
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MYCOBACTERIAL
HLA – DR2 ,-DR3 • Tuberculoid
leprosy
HLA – DQ1 • Lepromatous
leprosy
• Tuberculosis
• Leprosy
• Chronic inflammatory disease
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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
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SCABIES
HLA – A 11 • Increased
Susceptibility
• Resistant To
Treatment
• Multiple Nodular
Lesions
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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
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HLA ASSOCIATIONS WITH DRUGS
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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
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HLA ASSOCIATION WITH METABOLIC
DISEASES
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METABOLIC DISORDERS
Diabetes mellitus HLA-DR2,-DR6,-DR11
Myasthenia Gravis HLA-B8,-DR3,-DR1
Rheumatoid
arthritis
HLA-DR1, -DR4, -DR5,-DR8,-
DR12
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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.
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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
REFERENCES
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THANK YOU