LECTURE 3

MAJOR
HISTOCOMPATIBILITY
COMPLEX

Major Histocompatibility
Complex

Š Landsteiner discovered RBC types early

1900s
Š Proposed comparable WBC types
Š WBC antibodies developed in transplant
patients & multi-transfused

Major Histocompatibility
Complex

Š HLA = Human Leukocyte Antigens

Š Now known to be on all tissue cells
Š MHC = Major Histocompatibility Complex
„ also minor histocompatibility complex (mhc)
Š MHC has primary and secondary loci

1
 Major Histocompatibility
Complex
Š Genes on short arm of chromosome #6
„ ABO types on chromosome #9
„ Ig on 2, 14, & 22; TCR on cx7 & 14
„ 3500 kbp ~ total genome of E.coli bacteria
Š Multiple alleles
„ Simple Mendelian inheritance
„ 1 set from Mom & 1 set from Dad
„ Co-dominant expression
„ Linked set – minimal cross-overs or translocations

Major Histocompatibility
Complex

Š MHC class I = HLA-A, HLA-B & HLA-C

Š MHC class II = HLA-DP, HLA-DQ, &
HLA-DR
Š MHC class III = Complement factors C2, C4,
& Factor B

Major Histocompatibility
Complex
Short Arm of Chromosome #6
Centromere
II III I

DP DQ DR C2 C4 Bf B C A
~1000bp ~1000bp ~2000bp

2
 Major Histocompatibility
Complex
Š MHC-I found on all nucleated cells &
platelets (not mature RBC)
Š MHC-II found on Immune Response cells
„ B & T cells
„ Macrophages & other APC
„ Others induced during Immune Response

Major Histocompatibility
Complex
Š MHC-I consists of 2 glycopeptide chains
„ Alpha (α) chain is 338 amino acids long
„ ~281 aa extracellular
z 3 domains α1, α2, α3 about 90aa each
z α1-α2 regions – hypervariable – binding site
„ ~25 transmembrane
„ ~30 intracellular tail (heavily phosphorylated)

Major Histocompatibility
Complex
Beta (ß) chain is invariant - same in all
individuals
„ Gene on chromosome #15
„ Non-covalently bound to α chain between α2 and
α3 domains
„ 44kDa
„ Not transmembrane

3
 Major Histocompatibility
Complex
Š MHC-II consists of 2 glycopeptide chains
Š Both transmembrane
„ Alpha (α) chain 33-35 kDa
„ Beta (ß) chain 26-28 kDa
Š 10-20 copies of MHC-II per cell membrane
Š Increased with immune activation

Major Histocompatibility
Complex
Š MHC-II chains non-covalently attached to
each other
Š α1 & α2 domains
Š ß1 & ß2 domains
Š Space between and including α1 and ß1
hypervariable binding site

Major Histocompatibility
Complex
Š MHC-I and MHC-II involved in antigen
presentation to the Immune system
Š Hypervariable regions “hold” antigen for
Lymphocytes to “see”
Š Some hold better than others
Š Best hold gets to present to the Immune
System for reaction

4
 Major Histocompatibility
Complex

Š MHC-III not truly part of HLA

Š Complement factors C2, C4 and Factor B
Š Non-variant gene products

Major Histocompatibility
Complex
Š Highly polymorphic genes
Š Each human relatively unique if look at total
major and minor complex
Š Certain disequilibrium expressions (higher
than predicted % of population) – selective
advantages?

Major Histocompatibility
Complex
Š HLA & Disease
Š Relative Risk factors (1 = norm)
Š Certain HLA types linked to higher than
normal risk to develop disease
Š Others linked to slow, poor or non-reactivity
to certain antigens

5
 Major Histocompatibility
Complex
Š HLA-B27 linked to Ankylosing Spondylitis
„ 87% of patients are B27+ (males)
„ Reiter’s Syndrome (arthritis) Risk Factor 37x
Š DR2
„ Multiple Sclerosis 4x
„ Disseminated Leprosy 5x
„ Goodpasture’s Syndrome 16x

Major Histocompatibility
Complex
Š HLA-DR3
„ Addison’s Disease – 6x
„ IDDM – 2x
„ w/ DR4 IDDM – 8x
„ w/ DQw8 IDDM –100x

Major Histocompatibility
Complex
Š HLA-DR4
„ IDDM – 3x
„ w/ DR3 IDDM – 8x
„ Rheumatoid Arthritis – 5x

6
 Major Histocompatibility
Complex
Š HLA-A3/B4 – Idiopathic hemochromatosis
Š HLA-B8/DR3/DQw2a homozygous
„ Poor responder to Hepatitis B
„ High fatality rate
Š HLA-B5 - low response to Tetanus Toxoid in
vaccine (& toxin)

Major Histocompatibility
Complex
Š HLA-B7 or HLA-B8 higher incidence of cat
allergies
Š HLA-A2 or HLA-A28 high incidence of
ragweed allergies

Major Histocompatibility
Complex
Š Utilization in medicine
„ Transplant tissue typing
„ Transfusion therapy
„ Paternity testing
„ Disease predictions
z Preventative measures can be implemented
„ Insurance Ratings or Treatment Protocols
z Ethical Issues!!!