 In defense of the host, the immune system

must differentiate between foreign proteins

and “self-proteins.”
 Surface display proteins are used as
markers of “self.”
 rejection or acceptance of grafts was
dependent on “self ” markers mapped to a
gene cluster on chromosome 6 called the
major histocompatibility complex (MHC).
 In humans, the MHC is called the human
leukocyte antigen (HLA) complex
(chromosome 6)
 transfusion reactions
 organ transplantation,
 autoimmunity,
 their most important role is antigen
presentation to T cells
 HLA molecules control susceptibility or
resistance to infection, the generation of
autoimmune responses, and antibody-
mediated and cell-mediated responses.
 Antigen Presentation

T Cell

TCR

Peptide-
MHC
Complex
APC
Major Histocompatibility Complex

 Chromosome 6 gene region encoding the antigen presenting

molecules (MHC molecules)
 Highly polymorphic genes (variable alleles)
 Play a central role in immune response to protein antigens
 Antigenic peptides bind to MHC molecule
 MHC molecules serve as ligands for T cell recognition
 Products are expressed on the surface of a variety of cells (All
nucleated cells,APCs, B cells etc.)
 Genes that control graft rejection
 MHC Control Graft Rejection
Skin
MHC-a Grafting MHC-a
No Graft
Rejection

Donor Recipient

Inbred mice – genetically identical (syngeneic)

Skin
MHC-a Grafting MHC-b
Graft
Rejection

Donor Recipient

Genetically different (allogeneic)

Properties of MHC Genes
 Class I and class II MHC genes encode two groups of
structurally distinct but homologous proteins
 Class I MHC present peptides to CD8+ T cellswhile
Class II MHC present peptides to CD4+ T cells
 MHC genes are codominantly expressed in each individual
 Most polymorphic genes present in every species analyzed
 250 alleles for some HLA loci
 MHC Haplotype
 Total set of MHC alleles present on each chromosome
 Human HLA alleles are assigned numerical designations
 Ex.HLA-A2,HLA-B5,HLA-DR3 etc.
 are expressed on nucleated cells in the
body, but some are secreted proteins that
augment an inflammatory response.
 the HLA gene complex is subdivided into
› class I, II, and III regions
 pseudogenes are coding sequences that
contribute to the genetic diversity of HLA
molecules.
 subdivided into three major loci
› HLA-A,
› HLA-B
› HLA-C
 minor loci consisting of HLA-G, HLA-E, HLA-F,
HLA-H, and HLA-J
 MHC class I chain–related genes (MIC)
 The major class I loci (A, B, and C) present
antigens to CD8 T cells.
 Expression of MIC marks the cell for destruction
by CD8 and NK cells.
 Minor loci have various immunologic
functions.
 HLA-E
› interacts with CD94 and NKG2 receptors on
natural killer (NK) cells to augment or inhibit
NK cell function.
 HLA-G
› is found in high concentrations on the
surface of extravillous cytotrophoblast and
the placenta.
› The role of HLA-G in pregnancy is unclear,
but it may shift immune responses from Th1
to Th2.
 Class II gene products are induced and
expressed on monocytes, macrophages,
dendritic cells, and B cells.
 Within the class II region are three loci
(DP, DR, and DQ) involved in antigen
presentation.
 Class II molecules present antigens to
CD4Th1 and CD4Th2 cells.
 Other genes in the class II region code for
proteins that are important in antigen
processing.
 Class I molecules comprise of:
› single glycosylated α-chain (394 amino acids),
› β2- microglobulin (94 amino acids)
 The class I protein consists of:
› two intracellular domains - attach the molecules to the cell
membrane and extend into the cytoplasm.
› three extracellular domains—designated α1, α2, and α3

 The α1- and α2- domains

› form an antigen-binding cleft used to present antigens to T cells
› the binding cleft accommodates only small peptides containing
8 to 12 amino acids.
 Alpha3 domain stabilizes interaction bet. Class I and Tcell
 Flexing of unbound peptides and side chains within the
binding cleft creates a three-dimensional epitope structure
that is recognized by T cells.
Class I MHC Molecules
 2 polypeptide chains
  subunit (heavy chain) – 44 kD (40 polypeptide + 4 oligosaccharide)
  subunit (light chain) – 12 kD (encoded by gene in chromosome 15)
  subunit is divided into 4 domains:
 The class II region has three major loci (DP, DQ,
and DR).
 Class II molecules consist of heavily
glycosylated α- and β-chains.
 the α-chain is larger (30–34 kiloDaltons [kDa])
compared with the β-chain (26–29 kDa).
 An antigen-binding cleft comprises the α1-
and β1-domains
 All class II antigens bind at the same anchor
positions and are much larger than class I
antigens (10–30 amino acids) and protrude
from either end of the cleft.
Class II MHC Molecules
 2 non-covalently associated subunits
  subunit (32-34 kD) – more glycosylated
  subunit (29-32 kd)
 Encoded by 2 separate MCH genes
 Both are polymorphic
Class I molecules are composed of a Class II molecules are composed of a
polymorphic α-chain noncovalently polymorphic α-chain noncovalently
attached to the nonpolymorphic β2- attached to a polymorphic β-chain.
microglobulin (β2m). The α-chain is
Both chains are glycosylated;
glycosylated; carbohydrate residues
are not shown. carbohydrate residues
are not shown.
 The class III region has 62 genes, which
have diverse functions.
 Most class III gene products are not
membrane proteins but are secreted
into the environment.
 Products include three complement
components (C4a, C4b, C2 and the
tumor necrosis factor (TNF).
 A set of HLAs (HLA A, B, C, DP, DQ, and DR)
on the same chromosome is called a
haplotype.
 The genotype of each individual consists of
two haplotypes. One set of HLA genes (N=6)
is inherited from the father, and the other
haplotype (N=6) is inherited from the mother.
Both haplotypes are co-dominant and
expressed on cells
 Crossing over of parental haplotypes and
DNA recombination allows individual genes
or parts of genes to transfer from one
chromosome to another without any loss of
function.
MHC I are Codominantly Expressed
 Three alleles (variants) are inherited from each parent
simultaneously
 Total of six different Class I MHC molecules on the cell surface
 Homozygous individuals has six different Class 1 MHCs
Codominant Expression of MHC I and
II

 Heterozygous individual has 12 different combinations

 The inheritance of duplicate genes provides a
survival advantage to heterozygotes.
 All HLA molecules can present antigens to T cells,
but each HLA molecule binds a different range
of antigens.
 In effect, the inheritance of paternal and
maternal haplotypes
› doubles the antigen-presenting capability of the host
› increases the probability that most individuals within a
species will be heterozygotes.
 Heterozygotes at an HLA locus are more resistant
to disease than are homozygotes
 they have a more varied repertoire of antigen-
presenting HLA molecules.
 Provides Additional genetic diversity
critical to the disease resistance
 Each variant of a polymorphic gene is
called an allele.
 2,000 polymorphic alleles in Class 1
region
 900 in class II
 SNPs are single base pair changes in
genes coding for each HLA allele. SNPs
create additional alternative forms of
each allele.
 Allelic polymorphism and SNPs are
associated with nonsynchronous
amino acid substitutions in the α-
helical sides of the binding cleft or β-
strands forming the floor of the cleft.
 A change in the binding cleft alters the
pattern of antigens binding to the
allele
 Polymorphic residues of human HLA
molecules.
 In the class II molecule shown (HLA-DR),
essentially all the polymorphism is in the β-
chain.
 Allelic polymorphism
› is a response to the constant and continuing evolution of
microbes which is essential to the survival of the species
 The presence of different alleles presenting a wide
range of antigens from the same microbe ensures that
some members of a species will survive the microbial
infection.
 Microbes that express an HLA allele would be
considered “self ” and evade immune detection.
 As a consequence of infection, significant population
mortality may occur among individuals carrying the
allele.
 Individuals expressing other HLA polymorphic alleles
within the same loci would be unaffected.
 T cells determines an individual’s resistance or
susceptibility to microbial infections.
 self-limiting hepatitis B - expression of HLA-DR13
 Individuals homozygous for DR13
› more efficient presentation of hepatitis antigens,
› strong vigorous CD4 response,
› accelerated viral clearance
 Chronic hepatitis B infections develop in
individuals expressing other HLA DR molecules.
 Individuals with (DRB1*1501) molecules have a
high risk for developing pulmonary tuberculosis.
› It is assumed that these class II molecules cannot
present mycobacterium antigens to CD4Th1 cells.
 The CD1 family of genes is involved in
antigen presentation.
 chromosome 1
 CD1 molecules present highly conserved
glycolipids to CD4Th1 cells.
 Glycolipids include mycolic acid, glucose
monomycolate, phosphoinositol
mannosides, and lipoarabinomannan
derived from the Mycobacterium species
that cause tuberculosis and leprosy.
 Two families of CD1 molecules exist:
› (1) Group I consists of CD1a, CD1b, and CD1c.
› (2) group II- CD1d
 CD1a - thymocytes, dendritic cells, and
Langerhans cells.
 CD1b - monocytes and macrophages.
 CD1c - circulating B cells,the splenic mantle
zone, and tonsillar B cells.
 CD1d - Monocytes, macrophages,
dendritic cells, B cells, and some
nonlymphoid cells
 is a form of severe combined
immunodeficiency (SCID)
 individuals lack class II molecules on the
surface of B cells and monocytes due to
mutations
 Mutations prevent the docking of regulator
factor X (RFX) and class II transactivator (CIIT)
with the promoter genes.
 Children with BLS have repeated infections with
Candida albicans or Pneumocystis jiroveci.
 Common childhood viral infections with
respiratory syncytial virus (RSV) or
cytomegalovirus (CMV) are fatal.
 Without hematopoietic stem cell transplantation,
infants with this syndrome die within the first year of
life.
 Aggressive antibiotic therapy is indicated for
suspected microbial and viral infections.
Diseases Associated with MHC Genes
MHC Alleles and Allergy

 The DRB1*0101 allele in the Hutterites and the DRB1*0102

allele in African Americans confer risk for cockroach
sensitization
• J Allergy Clin Immunol. 2000 May;105(5):960-6.

 A novel association between DQB1 0603-DRB1 13 and birch

• allergy
• Allergy. 2007 Sep;62(9):991-8..

 The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be a

genetic marker for the development of TDI (toluene
• diisocyanate-induced asthma) -induced asthma
MHC Alleles and SLE

• HLA-A*11 and novel associations in Malays and

Chinese with systemic lupus erythematosus
Mohd-Yusuf Y., Phipps M., Chow SK., Yeap, S., 2011
Immunology Letters 2011

HLA-DRB1 (DRB1*0701,
DRB1*1601- 1606,DRB5*01-02,
DQB*05) are
significantly associated with SLE
in both Malay and Chinese pts
MHC Alleles and HCV Infection

• Yosri et al. (2011) The association of HLA class

II DR B1 alleles with HCV infection in Egyptian
children. Arab Journal of Gastroenterology 12:
25–28

– HLA DRB103 was present in nearly half of

patients,
– while HLA DRB115 frequency was
significantly reduced among the cases
in comparison to control subjects.
MHC Alleles and Myasthenia Gravis

• Association of HLA-A in Autoimmune Myasthenia Gravis

with Thymoma. Vandiedonck C, Raffouz C, Eymard B,
Tranchant C, Dulmet E, Krumeich, Gajdos P, and
Garchon HJ. Journal of Neuroimmunology 201 (2009)
120-123.
• MG associated with thymus follicular
hyperplasia involves A*01 (HLA-A) in linkage
disequilibrium with causative alleles on 8.1
MHC haplotype
• Modest increase of A*25 but large effect
on A*02 in patients with B2 thymomas
 The human leukocyte antigen (HLA) complex on
chromosome 6 has three regions that code for antigen-
presenting molecules.
 Three major class I and class II loci are present within the
coding regions.
Major loci within the class I region produce glycoproteins
that present antigens to CD8 cells.
 Major loci within the class II region produce glycoproteins
that present antigens to CD4 cells.
Regions outside the HLA complex code for molecules that
present highly conserved molecules.
 Each individual has two sets of HLA molecules. One is
inherited from the mother and the other from the father.
 Heterozygosity, allelic polymorphism, and single
nucleopeptide polymorphisms (SNPs) ensure that some
members of the species will survive microbial infections.