Effects of Vitamin D and Retinoic Acid on HLA-DR Expression

Dissertation
THE EFFECTS OF VITAMIN D AND RETINOIC ACID ON THE
EXPRESSION LEVEL OF HLA-DR

Abstract
The term MHC refers to a major histocompatibility complex molecule which is used to
control and monitor the cell-mediated adaptive process. There are major two kinds of the
immune system used to exist in the human body, for example, adaptive immunity and innate
immunity. It is identified that MHC molecules support to examine T-cell antigen receptors
and it also provides a platform for indicating peptide antigens. Moreover, human leukocyte
antigen also helps for controlling the amount of MHC presented antigens which destroy
cancerous cells. This research paper identified the key factors linked with MHC molecules
and provided in-depth analysis of the research topic. There are two types of MHC classes
used such as class I and class II and this study also compared both MHC class I and class II.
The molecules of MHC class I consists of one membrane spanning alpha chain which is
encoded by the MHC gene. MHC class II molecules, it consists of two membrane-spanning
chains, alpha and beta, but their sizes are similar. Several molecules of MHC are directly
linked with inflammatory diseases and also increased risk of autoimmune. The study
involved vitamin D and KG-1 cells along with ATRA. Vitamin D is defined as “sunshine
vitamin” which is produced in the skin, in response to the direct sunlight. It is analysed that
that RA (Retinoic Acid) plays a vital role in the homeostatic control of the human immune
system In this research study, there are various kinds of research methodologies will be used
for example qualitative and quantitative research design, sampling technique, data analysis
approach, data collection method. Moreover, a secondary process will be used for obtaining
related data and information about the research topic. This paper shows the impact of vitamin
D and critically reviewed MHC molecules. It is concluded that Retinoic acid plays a critical
role in modulating the process of switch between the regulatory and inflammatory T-cells. It
is suggested that mutual communication exists between the two pathways where activation of
one pathway stops the other pathway from improving the level of expression. In future

research, the authors will describe the kinds of communication exists between HLA-DR and
vitamin D.
Keywords: vitamin D, MHC, HLA-DR, T-cells, and immune system

1. Introduction Chapter
1.1 MHC molecules and immunity
The cell-mediated adaptive immunity system is basically regulated by MHC, which is a
Major Histo-compatibility Complex molecule (Giles et al. 2015). The immune system of the
body fights the pathogens that succeed in invading the normal tissues. Immune system
protects the human body in various ways against bacteria, viruses, parasites, cancerous cell or
any other. Pathogens enter into the body in an invasive way.Two types of immune system
exist, innate immunity and adaptive immunity. Innate immune defences are mediated by
white blood cells or WBC, such as granulocytes, monocytes/macrophages and natural killer
cells, and by antibacterial proteins, such as acute phase and complement proteins, circulating
in blood.But, in case of adaptive immunity, some specific defences against an invader are
developed (Rock, Reits and Neefjes 2016). However, several forms of adaptive immunity are
there and they are humoral and cell mediated. In order to destroy the antigens, antibodies
appear in the body fluids in case of humoral adaptive immunity system but, in cell mediated
immunity system cells can destroy other cells become active. They destroy all the disease
infected cells (Rock, Reits and Neefjes 2016).
1.1.1 Function of MHC
Some specific functions of MHC molecules have been found by the researchers. MHC
moleculeshelps to introduce T-cell antigen receptors (and, in parallel, B-cell antigen receptors
for B cells) at an early stage. Inside the human body cells, proteins are broken down into
short fragments (Giles et al. 2015). Those short fragmented proteins can be displayed as
peptide antigens by MHC molecules. The self peptide, derived from the own proteins, as well
as the foreign peptides derived from the invading pathogens is displayed by MHC molecules

(Rock, Reits and Neefjes 2016). HLA (human leukocyte antigen) present in the MHC of
human body also helps in monitoring the amount of MHC-presented antigens that destroys
cancerous cells which displays increased amount of self-antigens (Moutsianas et al. 2015).
There are a vast number of potential peptide targets but the number of MHC proteins is
limited and due to this purpose MHC proteins are highly effective in binding several types of
peptides. Moreover, MHC proteins have the capability of binding peptides of different kinds
and even of different structures. Due to this unique property, MHC proteins are different from
other proteins or molecules.Tissue allorecognition is another function of MHC and it plays a
major role in preventing successful transplantation of organ (Moutsianas et al. 2015).
1.1.2MHC and antigen presentation
MHC is useful in controlling the process in which the immune system of human body detects
as well as responds to some specific antigens. The MHC molecules also control the antigen
specificity of T-cell recognition (Giles et al. 2015). There are two different classes of MHC
molecules, class I as well as class II. Both the classes have similarity in function of involving
the delivery of very short peptides into the surface of cell recognition and it basically takes
place by CD8+ and CD4+ T cells respectively. It is possible to stimulate some specific T-
cells by MHC class I which is basically located on all cells which are nucleated(Cho et al.
2015).
1.1.3 Difference between MHC class I and MHC class II
MHC is known to be highly polymorphic and in the immune function, the role of it
significant. In E. jankowskii, low level of MHC polymorphism was revealed and it was
similar to that in E.Cioides. There is a difference between the two classes of MHC. The
properties are not similar. The class I is the glycoproteins, which are expressed upon the
surface of all the nucleated cells. The main role of the class I MHC is the presentations of

peptide antigens into the TC (cytotoxic T) cells. The molecules of MHC class I consists of
one membrane spanning alpha chain which is encoded by MHC gene and one beta chain,
which is encoded by the beta2 microglobulin gene (Cho et al. 2015). It also presents foreign
intracellular antigens. But, in case of MHC class II molecules, it consists of two membrane
spanning chains, alpha and beta, but their sizes are similar and both are produced by the
MHC genes. The glycoproteins of MHC class II is present only on some specialized antigen
presenting cells. It also presents 14-18 amino acid peptides which is greater than MHC I. The
class II of MHC also presents foreign extracellular antigen that induces antibody production
as well. The inflammatory response increases the blood flow to the inflammatory area and it
brings immune cells to the site(Van der Meijden et al. 2016). All these properties distinguish
MHC class II from the properties of the MHC class I. Again, MHC class II is basically is a
class of major histo-compatibility complex molecules. These are generally found only on
antigen-presenting cells that includes mononeuclear phagocytes, dendritic cells, etc. All the
cells are extremely important in initiating the immune responses. MHC, the group of genes is
also useful in encoding the proteins found on the surface of cells, and it helps in the
recognition of antigens. At the same time it also determines the histo-compatibility (Giles et
al. 2015). MHC molecule is generally found in human chromosome and can be termed as
human leukocyte antigen (HLA).

Figure 1: Structure of HLA class II molecules.
The schematic diagram illustrates the different regions of the HLA-DR1 class II molecule.
Each of the class II α and β chains has four domains: the peptide binding domain (α1 and β1),
the immunoglobulin-like domain (α2 and β2), the transmembrane region (TM), and the
cytoplasmic tail (CYT)
1.1.4 MHC and Autoimmunity
Some molecules of MHC are directly associated with inflammatory diseases as well as with
the increased risk of autoimmune. In the year 1967, it was first found that MHC HLA-B
antigens increased frequency among the patients having Hodgkin’s lymphoma. Apart from
that, multiple sclerosis, rheumatoid arthritis, Crohn’s disease and some other health

conditions of human being are also associated with some specific MHC molecules(Hauser et
al. 2017).In an analysis, conducted by the association of MHC disease revealed that a
susceptibility of shared disease is there to the alleles that arise from HLA-DR4 haplotypes.
Simultaneously, the analysis indicates that there is a common as well as disease specific
association between autoimmunity and the MHC. The exact and specific mechanism behind
the autoimmunity and MHC molecules has not properly been found in the researches but it
potentially reflects a breakdown in tolerance to self-antigens in the antigen presentation of
normal MHC class II. Therefore, some specific class II alleles work as the determinants of
auto-antigen targeting (Cho et al. 2015).
1.1.5 MHC and tissue allorecognition
1.1.5.1Transplant rejection
Allorecognition is basically the capability of an organism that helps in distinguishing its
tissues from those of another organism. This distinguishing is possible within the same
species also plays the important role in the implication of transplantation. Various risks are
there in organ transplantation and one of them is alloresponse, and in this condition,
histoincompatible antigen is identified as well as recognized and it also produces an adaptive
immune response by employing allospecific T-cells (Hauser et al. 2017). All these things can
lead to the direct rejection of all the tissues that are transplanted. But, the direct involvement
of MHC into the mechanism of allorecognition helps in this regard. Here, the T-cell identifies
the determinants on the donor. MHC molecules always display a type of antigenic
determinant that is termed as epitope. T cells have the ability to identify the epitopes
presented by particular allelic variant of MHC molecules. But, if the epitopes are presented
by allelic variants of another MHC molecule, then it is not possible for the T-cells to
recognize those (Van der Meijden et al. 2016).