HLA AND SKIN DISEASES

Dr.Rohit Kumar Singh

Resident ,MD Dermatology

Base Hospital ,LKO

CONTENTS

Introduction

HLA structure and function

HLA and disease association

Inflammatory disease

Autoimmune disease

Infections

Drugs

Metabolic diseases

Conclusion

Referrences

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

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

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)

HLA STRUCTURE

Region B C D

Gene

product

HLA - B HLA- C HLA - D

MHC CLASS I

Minor genes include E ,F ,G

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

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

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

HLA STRUCTURE

Region C4 C2 BF

Gene

product

‘C’ PROTEINS TNF –α,

TNF-β

MHC CLASS

III

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

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.

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

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).

INFLAMMATORY DISEASES

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

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

AUTOIMMUNE DISEASE

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

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

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

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

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

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

HLA ASSOCIATION WITH INFECTIONS

MYCOBACTERIAL

HLA – DR2 ,-DR3 • Tuberculoid

leprosy

HLA – DQ1 • Lepromatous

leprosy

• Tuberculosis

• Leprosy

• Chronic inflammatory disease

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

SCABIES

HLA – A 11 • Increased

Susceptibility

• Resistant To

Treatment

• Multiple Nodular

Lesions

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

HLA ASSOCIATIONS WITH DRUGS

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

HLA ASSOCIATION WITH METABOLIC

DISEASES

METABOLIC DISORDERS

Diabetes mellitus HLA-DR2,-DR6,-DR11

Myasthenia Gravis HLA-B8,-DR3,-DR1

Rheumatoid

arthritis

HLA-DR1, -DR4, -DR5,-DR8,-

DR12

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.

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

THANK YOU