The document discusses the role of major histocompatibility complex (MHC) or human leukocyte antigen (HLA) in organ rejection, emphasizing the importance of classical class I and II molecules in transplantation. It highlights how both HLA and non-HLA antigens contribute to acute and chronic allograft rejection, necessitating the detection of anti-HLA antibodies post-transplant. Additionally, it explains the genetic characteristics of MHC, its evolution, and the structure and function of class I and II molecules in immune responses.

1. Role of Major
Histocompatibility Complex
(MHC) or HLA in Organ Rejection
BY Dr. S.SREEREMYA
FACULTY OF BIOLOGY

2. • MHC genes evolve through duplication, followed by
diversification, co‐evolution, and sequence exchange. The
focus, for HLA in transplantation, has been the specific
classical class I and class II human leukocyte antigen (HLA)
molecules and alleles. Importantly, anti‐HLA antibodies
developed after the organ transplants play a role in acute
and chronic allograft rejection, highlighting the need to
detect these antibodies in a clinically relevant manner.
Although the immune response to HLA antigens plays a
pivotal role in allograft rejection, evidence shows that
non‐HLA antigens also contribute to the pathogenesis of
acute and chronic rejection, which limits long‐term graft
survival of the solid organ transplants.

3. • The HLA complex genes and their protein products have been
divided into three categories (I, II, and III) on the basis of their tissue
distribution, structure, and function. MHC class I and II genes
encode co dominantly expressed as HLA cell surface antigens, and
class III genes encode several components of the complement
system; all share important roles in immune function (Mark, 1990).
Class I MHC antigens are present on all of tnucleated cells and are
composed of a 40-kd transmembrane α heavy chain encoded by
genes of the HLA-A, HLA-B, or HLA-C loci on chromosome 6; the α
heavy chains are associated noncovalently with a 11-kd protein, β2-
microglobulin, encoded by a gene on chromosome 15(Elzinga et
al.,1992). Additional (nonclassical) class I molecules, like those
encoded by the HLA-E, -F, -G, -H loci, have been delineated and
show limited variability and tissue distribution.

4. • The precise functions of these molecules are not yet clearly understood,
although they have been implied in presenting the carbohydrate and
peptide fragments to γδ T cells and mother's immunological tolerance of
the foetus. MHC class II antigens are expressed only on the B lymphocytes,
activated T lymphocytes, monocytes, macrophages, Langerhans cells,
dendritic cells, endothelium, and epithelial cells. Class II molecules are
heterodimers specifically composed of non covalently associated α and β
polypeptide chains chains encoded by the genes of the HLA-D region.
There are 3 major class II proteins designated as, HLA-DP, HLA-DQ, and
HLA-DR. Class III genes are located between the HLA-B and HLA-D loci and
determine the structure of three main components of the complement
system: C2, C4, and factor B (Palestine et al., 1986). Class I MHC molecules
present cytoplasm-derived peptides, or intracellular parasites, principally
viruses; whereas the MHC class II molecules bind peptides derived from
extracellular proteins (Deray et al., 1992). HLA class I and II molecules are
recognized by CD8 and CD4 positive T cells, respectively. Also, NK cells may
recognize the HLA classical and non classical type I molecules (Austin et
al., 1989).

5. • GENETIC CHARACTERISTICS OF MCH
• The MHC is a large chromosomal region with over 210
coding loci. The MHC region contains class I and II
genes, which control all the specific immune
responses, but it also comprises many other genes that
influence growth, development, reproduction, odour
and olfaction. Among the MHC loci that control the
immune system are class I and II MHC loci (‘classical’
MHC genes), which are the most predominantly
polymorphic genes known among vertebrates. Class I
and II MHC loci are closely rakished within the MHC
cluster in many species, such as mice and humans
(Andersen et al., 1991).

6. • In humans there are six class I loci (e.g. A, B and C) and eight class II
loci (e.g. DP, DQ and DR), and in mice typically there are three class I
(K, D, and L) and 2 class II (A and E) loci. Each class II locus
comprises of multiple coding genes. In most species, the
polymorphism of MHC differs from one to over 100 alleles per
locus. The close linkage of the MHC loci on the same chromosome
means that each individual inherits their particular merged of MHC
alleles as a single unit or haplotype (closely related genes on a
chromosome have a low chance of recombination separating
them). The close linkage of MHC loci suggests that they have a
much common ancestor, and that the close physical linkage on the
same chromosome has been maintained by natural selection. MHC
loci are not always found in much close linkage. In zebra fish and
African clawed frogs, for example, the class I and II loci are located
on different chromosomes (Feldt et al., 1990). Class I molecules

7. • Class I molecules present the small peptides to CTLs,
effectively advertising the contents of the body’s cells to
the immune system (Assan et al., 1994). These peptides are
commonly self peptides; however, if a cell becomes
infested with a virus or other type of intracellular parasite,
then the infested cell presents foreign peptides from the
invading parasite. CTLs probe the surface of cells, searching
for evidence of an infection. Each CTL has the unique,
highly specific T-cell receptor (TCR) on its surface that binds
to MHC–antigen ramifies. CTLs also have CD8 adhesion
molecules on their surface that stabilize the interaction
between T cells and the presenting the cell by binding to
class I MHC molecules (Mihatsch et al., 1991).

8. • Journal of Research in Human Anatomy and
Physiology ,Role of Major Histocompatibility
Complex (MHC) or HLA in Organ Rejection,
Dr.S.Sreeremya , 2019.Vol 1(1):1-10.