Imuno

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The translation from genetic knowledge to a molecular understanding of disease is contributing to the development of
improved diagnostic and therapeutic products. Here, we examine the progress in molecular understanding of autoimmune
disease that has been facilitated by genetic approaches, from candidate gene studies to genetic linkage and, more recently,
genome-wide association studies. We concentrate primarily on progress in the genetics of type 1 diabetes, multiple sclerosis,
and systemic lupus erythematosus, and draw attention to parallels and contrasts between these diseases, other autoimmune
diseases, and other immune diseases. We discuss selected gene loci where functional data have contributed to our
knowledge of molecular mechanisms of disease.

Autoimmune conditions are multifactorial in their cause, with a mixture of genetic and
environmental factors often playing a role.
As multifactorial conditions are partly caused by genetic factors, autoimmune conditions tend to
run in families. Environmental factors such as viruses or sunlight then trigger an immune
response in genetically susceptible individuals.
When one individual in a family has an autoimmune condition, other family members are then
at an increased risk of autoimmunity. However, genetically susceptible individuals do not always
go on to develop an autoimmune condition.
There are three main groups of genes that are thought to raise the risk of autoimmune diseases
developing. These genes are associated with T cell receptors, immunoglobulins and the major
histocompatibility complexes. T cell receptors and immunoglobulins are important for the
recognition of antigens and are highly variable to allow for the massive variation in antigens that
the immune system needs to be able to target. However, this number of variations can also give
rise to the development of lymphocytes that are capable of autoreactivity.

Over the years, various researchers such as McDevitt, Nepom, Bell and Todd have provided
evidence suggesting that some MHC class II allotypes are strongly associated with certain
conditions. Examples include:
HLA DR2 is positively associated with Systemic Lupus Erythematosus (SLE), multiple sclerosis
and narcolepsy, while it is inversely associated with type I diabetes mellitus.
HLA DR3 is strongly associated with myasthenia gravis, SLE, type I diabetes and Sjögren's
syndrome.
HLA DR4 is strongly associated with Type 1 diabetes mellitus, pemphigus vulgaris and
rheumatoid arthritis.
Correlations between autoimmune conditions and MHC class I molecules are less common, but
one notable example is the association between ankylosing spondylitis and HLA B27.
In terms of genes that exist outside of the MHC complex, genes that contribute to the
development of autoimmunity are currently being investigated in animal models of diabetes and
SLE. One recent development is that the PTPN22 gene, which codes for protein tyrosine
phosphatase, non-receptor type 22, is associated with various different autoimmune conditions
including SLE, rheumatoid arthritis, type 1 diabetes, vitiligo, psoriatic arthritis and Grave’s
disease.

Autoimmune diseases are the result of an interplay between predisposing genes and triggering
environmental factors, leading to loss of self-tolerance and an immune-mediated destruction of
autologous cells and/or tissues. Genes in the HLA complex are among the strongest
predisposing genetic factors. The HLA complex genes primarily involved are most often those
encoding the peptide-presenting HLA class I or II molecules. A probable mechanism is
preferential presentation by the disease-associated HLA molecules of peptides from autoantigens
to T cells. Recent studies have shown, however, that other genes in the HLA complex also
contribute. Taken together, available evidence suggests that the HLA complex harbour both
disease predisposing genes which are quite specific for some autoimmune diseases (e.g. HLA-
B27 for ankylosing spondylitis) and others which may be more common for several diseases.
This will be briefly reviewed in the following.

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any
disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent
examples include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus
erythematosus (SLE), Sjögren's syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's
thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid
arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS).
Autoimmune diseases are very often treated with steroids.[1]

Genetic factors[edit]
Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is
associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop
autoimmune diseases.
Three main sets of genes are suspected in many autoimmune diseases. These genes are related to:
 Immunoglobulins
 T-cell receptors
 The major histocompatibility complexes (MHC).
The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to
recombination. These variations enable the immune system to respond to a very wide variety of invaders, but
may also give rise to lymphocytes capable of self-reactivity.

 HLA DR2 is strongly positively correlated with Systemic Lupus Erythematosus, narcolepsy[11] and multiple
sclerosis, and negatively correlated with DM Type 1.
 HLA DR3 is correlated strongly with Sjögren's syndrome, myasthenia gravis, SLE, and DM Type 1.
 HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1 diabetes mellitus, and pemphigus
vulgaris.
The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease
(Linda Wicker's extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin's linkage
analysis of susceptibility to SLE).
Recently, PTPN22 has been associated with multiple autoimmune diseases including Type I diabetes,
rheumatoid arthritis, systemic lupus erythematosus, Hashimoto’s thyroiditis, Graves’ disease, Addison’s disease,
Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis, and psoriatic arthritis.

An antibody (Ab), also known as an immunoglobulin (Ig),[1] is a large, Y-shaped protein produced mainly
by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic
bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via
the Fab's variable region.[2][3] Each tip of the "Y" of an antibody contains a paratope (analogous to a lock) that is
specific for one particular epitope (similarly analogous to a key) on an antigen, allowing these two structures to
bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for
attack by other parts of the immune system, or can neutralize its target directly (for example, by blocking a part
of a microbe that is essential for its invasion and survival). Depending on the antigen, the binding may impede
the biological process causing the disease or may activate macrophages to destroy the foreign substance. The
ability of an antibody to communicate with the other components of the immune system is mediated via its Fc
region (located at the base of the "Y"), which contains a conserved glycosylation site involved in these
interactions.[4] The production of antibodies is the main function of the humoral immune system.[5]

Antibodies are secreted by B cells of the adaptive immune system, mostly by differentiated B cells called plasma
cells. Antibodies can occur in two physical forms, a soluble form that is secreted from the cell to be free in
the blood plasma, and a membrane-bound form that is attached to the surface of a B cell and is referred to as
the B-cell receptor (BCR). The BCR is found only on the surface of B cells and facilitates the activation of these
cells and their subsequent differentiation into either antibody factories called plasma cells or memory B cells that
will survive in the body and remember that same antigen so the B cells can respond faster upon future
exposure.[6] In most cases, interaction of the B cell with a T helper cell is necessary to produce full activation of
the B cell and, therefore, antibody generation following antigen binding.[7] Soluble antibodies are released into
the blood and tissue fluids, as well as many secretions to continue to survey for invading microorganisms.
Antibodies are glycoproteins belonging to the immunoglobulin superfamily.[4] They constitute most of the gamma
globulin fraction of the blood proteins. They are typically made of basic structural units—each with two
large heavy chains and two small light chains. There are several different types of antibody heavy chains that
define the five different types of crystallisable fragments (Fc) that may be attached to the antigen-binding
fragments. The five different types of Fc regions allow antibodies to be grouped into five isotypes. Each Fc region
of a particular antibody isotype is able to bind to its specific Fc Receptor (except for IgD, which is essentially the
BCR), thus allowing the antigen-antibody complex to mediate different roles depending on which FcR it binds.
The ability of an antibody to bind to its corresponding FcR is further modulated by the structure of the glycan(s)
present at conserved sites within its Fc region.[4] The ability of antibodies to bind to FcRs helps to direct the
appropriate immune response for each different type of foreign object they encounter.[8] For example, IgE is
responsible for an allergic response consisting of mast celldegranulation and histamine release.
IgE's Fab paratope binds to allergic antigen, for example house dust mite particles, while its Fc region binds to
Fc receptor ε. The allergen-IgE-FcRε interaction mediates allergic signal transduction to induce conditions such
as asthma.[9]
Though the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely
variable, allowing millions of antibodies with slightly different tip structures, or antigen-binding sites, to exist. This
region is known as the hypervariable region. Each of these variants can bind to a different antigen.[2] This
enormous diversity of antibody paratopes on the antigen-binding fragments allows the immune system to
recognize an equally wide variety of antigens.[1] The large and diverse population of antibody paratope is
generated by random recombination events of a set of gene segments that encode different antigen-binding sites
(or paratopes), followed by random mutations in this area of the antibody gene, which create further
diversity.[8][10] This recombinational process that produces clonal antibody paratope diversity is called V(D)J or VJ
recombination. Basically, the antibody paratope is polygenic, made up of three genes, V, D, and J. Each paratope
locus is also polymorphic, such that during antibody production, one allele of V, one of D, and one of J is chosen.
These gene segments are then joined together using random genetic recombination to produce the paratope.
The regions where the genes are randomly recombined together is the hyper variable region used to recognise
different antigens on a clonal basis.
Antibody genes also re-organize in a process called class switching that changes the one type of heavy chain Fc
fragment to another, creating a different isotype of the antibody that retains the antigen-specific variable region.
This allows a single antibody to be used by different types of Fc receptors, expressed on different parts of the
immune system.

The T-cell receptor, or TCR, is a molecule found on the surface of T cells, or T lymphocytes,[1] that is responsible
for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules.
The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs
recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.[2]
The TCR is composed of two different protein chains (that is, it is a heterodimer). In humans, in 95% of T cells
the TCR consists of an alpha (α) chain and a beta (β) chain (encoded by TRA and TRB, respectively), whereas
in 5% of T cells the TCR consists of gamma and delta (γ/δ) chains (encoded by TRG and TRD, respectively).
This ratio changes during ontogeny and in diseased states (such as leukemia). It also differs between
species. Orthologues of the 4 loci have been mapped in various species.[3][4] Each locus can produce a variety
of polypeptides with constant and variable regions.[3]
When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T lymphocyte is activated through
signal transduction, that is, a series of biochemical events mediated by associated enzymes, co-receptors,
specialized adaptor molecules, and activated or released transcription factors.

The major histocompatibility complex (MHC) is a set of cell surface proteins essential for the acquired immune
system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. The main
function of MHC molecules is to bind to antigens derived from pathogens and display them on the cell surface for
recognition by the appropriate T-cells.[1] MHC molecules mediate interactions of leukocytes, also called white
blood cells (WBCs), which are immune cells, with other leukocytes or with body cells. The MHC determines
compatibility of donors for organ transplant, as well as one's susceptibility to an autoimmune disease via
crossreacting immunization. The human MHC is also called the HLA (human leukocyte antigen) complex (often
just the HLA). The MHC in mice is called the H-2 complex or H-2.
In a cell, protein molecules of the host's own phenotype or of other biologic entities are continually synthesized
and degraded. Each MHC molecule on the cell surface displays a molecular fraction of a protein, called
an epitope.[2] The presented antigen can be either self or non-self, thus preventing an organism's immune
systemtargeting its own cells. In its entirety, the MHC population is like a meter indicating the balance of proteins
within the cell.
The MHC gene family is divided into three subgroups: class I, class II, and class III. Class I MHC molecules have
β2 subunits so can only be recognised by CD8 co-receptors. Class II MHC molecules have β1 and β2 subunits
and can be recognised by CD4 co-receptors. In this way MHC molecules chaperone which type of lymphocytes
may bind to the given antigen with high affinity, since different lymphocytes express different T-Cell Receptor
(TCR) co-receptors.
Diversity of antigen presentation, mediated by MHC classes I and II, is attained in at least three ways: (1) an
organism's MHC repertoire is polygenic (via multiple, interacting genes); (2) MHC expression is codominant (from
both sets of inherited alleles); (3) MHC gene variants are highly polymorphic (diversely varying from organism to
organism within a species).[3] Major histocompatibility complex and sexual selection has been observed in male
mice making mate choices of females with different MHCs and thus demonstrating sexual selection.[4] Also, at
least for MHC I presentation, there has been evidence of antigenic peptide splicing which can combine peptides
from different proteins, vastly increasing antigen diversity.

In Immunity[edit]
Of the three MHC classes identified, attention commonly focuses on classes I and II. By interacting
with CD4 molecules on surfaces of helper T cells, MHC class II mediates establishment of specific immunity (also
called acquired immunity or adaptive immunity). By interacting with CD8 molecules on surfaces of cytotoxic T
cells, MHC class I mediates destruction of infected or malignant host cells, the aspect of specific immunity
termed cellular immunity. (The other arm of specific immunity is humoral immunity, whose relation to MHC is
more indirect.)

Protein tyrosine phosphatase, non-receptor type 22 (lymphoid), also known as PTPN22, is a protein that in
humans is encoded by the PTPN22 gene.[5][6][7] This gene can be expressed in different forms. PTPN22 affects
the responsiveness of T and B cell receptors, and mutations are associated with increases or decreases in risks
of autoimmune diseases.