This document discusses the HLA (Human Leukocyte Antigen) system and principles of tolerance. It describes that the HLA system is found on chromosome 6 and plays a key role in adaptive immunity by facilitating antibody production. It then explains the structure of MHC class I and II molecules and how they present peptides. The document also notes that HLA alleles are associated with tissue compatibility, autoimmunity, infectious diseases, and some provide protection against certain diseases. Finally, it states that individuals with highly polymorphic HLA alleles may be susceptible to diseases, while those with protective alleles acquire immunity and tolerance, making them more fit for survival.

1. HLA System and principles of tolerance
Prof. R. MUTHUPPANDI
PG and Research Department of Zoology
Vivekananda College
Tiruvedakam west
Madurai – 625 234
INDIA
Note: Applicable for M.Sc. Students

2. Human Leukocyte Antigen (HLA) System:
• Human Leucocyte Antigen (HLA) system (MHC in animals) is a set of proteins found on the short
arm of chromosome 6.
• HLA system has sole response in adaptive or antigen specific
immune response by facilitating Ab production.
• The HLA gene family is divided into three subgroups: class I, class II, and class III.
• HLA - class I, class II alleles are associated with specific immunity, tissue compatibility(during
transplantation), autoimmunity, and infectious diseases.
• HLA - class III alleles involve in the production of complementary proteins, cytokines, and code
for heat shock proteins.
`

3. Structure of MHC class I (MHC I):
1. MHC I is composed of α chain with three domains—α1, α2, and α3.
2. The α1 rests upon a unit of the non - MHC molecule β2 microglobulin (encoded on human
chromosome 15).
3. The α3 domain is transmembrane, anchoring the MHC class I molecule to the cell membrane.
4. The peptide being presented is held by the floor of the peptide binding groove, in the central
region of the α1/α2 heterodimer (a molecule composed of two non - identical subunits).
5. The genetically encoded and expressed sequence of amino acids, the sequence of residues, of the
peptide binding groove's floor determines which particular peptide residues it binds.
6. MHC I is classified into 3 major or classical alleles (HLA – A, B, and C), and 3 minor or non –
classical alleles (HLA – E, F, and G).

4. Structure of MHC class II (MHC II):
I. MHC class II is formed of two chains, α and β, each having two domains—α1and α2 and β1 and
β2—each chain having a transmembrane domain, α2 and β2, respectively, anchoring the MHC
class II molecule to the cell membrane.
II. The peptide binding groove is formed of the heterodimer of α1and β1.
III. MHC II is classified into 3 major or classical alleles (HLA – DR, DQ, and DP), and 2 minor or
non – classical alleles (HLA – DM, and DO).

5. Genetic organization of HLA system

6. HLA system and principles of tolerance:
1) HLA system is the highly polymorphic in the human genome.
2) From the population studies, it is resolved that some HLA alleles have protective association
with certain diseases (eg. HLA – DRB1*13:02, HLA – DRB1*04:06 and HLA – DQB1*06:04
alleles have protective association with cervical cancer), while others make possessor susceptible
to certain diseases (eg. HLA – B*2702, HLA – B*2705, etc. are associated with ankylosing
spondylitis).
3) So, the HLA protective alleles render resistance against various diseases, infections, and different
environmental hazards and thereby the possessive organism gets a wide range of tolerance.
4) In the course of evolution, the survival fitness is determined by the quality and quantity of HLA
(MHC) alleles in the individuals of the population.
5) The individuals with highly polymorphic HLA (MHC) alleles are either susceptible to various
diseases, adverse environments are eliminated from the population, while those with protective
MHC alleles acquire immunity (adaptive immunity) and become survival of the fittest, and are
selected by the nature leading to speciation.