Ian Torres de Lima

Reg N: 201404442
Honours Immunology 2 Assessment
Class Coordinator: Catherine Lawrence
21 August 2014
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Autoimmunity
Genetic contribution to the development of autoimmune
diseases, immune mechanisms of systemic lupus
erythematosus and type I diabetes
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Genetic contribution to the development of autoimmune diseases
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Autoimmunity is a issue with multifactorial basis. Genetic and environmental factors
may, together, negatively interfere in the immune regulatory mechanisms, thereby leading
autoimmunity. The immune regulatory mechanisms provide immunologic tolerance against
self and foreign antigens. Tolerance is a protection factor that avoids autoimmunity and
diseases of immunologic unbalance nature.
The immunologic system presents complex interactions between cells and tissue
structures. Those interactions are mediated by many proteins and cytokines, whose expression
are genetic dependant. Some polymorphisms of the codifying genetic material can lead
defective interactions that can generate immunologic tolerance errors promoting self-reactive
lymphocytes.
The technology developed in the latest decades has been providing a great apparatus for
genetic mapping. This enables the recognition of genomic sites with great variation rate.
Some genetic factors that were better described due to genetic mapping technology advances
will be discussed together with its clinical implications.
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MHC polymorphisms and autoimmunity
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MHC molecules are directly related to lymphocyte antigen recognition. Genetic
polymorphisms in HLA genes can represent different types of interactions between specific

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antigens, the MHC molecule and the lymphocyte receptor. Some of those interactions may
be favourable to the development of autoimmunity. Thereby is not unlikely that
polymorphisms of MHC molecules have strong relation to some autoimmune diseases. Some
MHC molecules are more effective in presenting some antigens, thereby if the antigen is self,
the presentation can be strong enough to elicit an autoimmune response. Studies comproves
that the incidence of autoimmune diseases is highly correlated with specific MHC
polymorphisms. However, the mechanisms underlying HLA genes and autoimmunity is not
well clear.
Class II MHC polymorphisms have a greater repercussion because this molecule is
related to CD4+ T cell activation. CD4+ T cells participate in both cell mediated and
humoral immunity. For this reason MHC II related autoimmunity can be systemic or local.
Autoantibodies that act against cytoplasmic and nuclear proteins (involved in DNA and RNA
processing) are related to systemic autoimmunity, in the other hand, autoantibodies specific
for some organs lead to local autoimmunity (Hewagama and Richardson, 2009), (Mok and
Lau, 2003).
MHC I and MHC II molecules are encoded by the following alleles situated in
chromosome 6: HLA-A, HLA-B, HLA-C and HLA-DQ , HLA-DR, HLA-DP, respectively.
The MHC peptide-binding cleft is codified by the most variable MHC alleles. Each
combination of alleles can alter the interaction between the MHC, the antigen and the T cell
receptor, thereby determining the specificity of the immune response to certain antigens. In
order to exemplify, a data from European-derived populations correlating the HLA allele
polymorphism to specific diseases shows that HLA-B27 type is strongly correlated with
ankylosing spondylitis (showing an odds ratio of 100-200) (Hewagama and Richardson,
2009), (Animesh and LOPEZ, 1990). There are many other examples.
The autoimmunity involving MHC is polygenic. The combination of polimorfisms in
both T cell receptors and MHC molecules must be in a favourable match to initiate
autoimmunity. T cells receptors (TCRs) are determinate by 3 possible gene rearranges
(capable of generating 10^15 different TCRs), V, D and J (Hewagama and Richardson, 2009)
(Hewagama and Richardson, 2009).
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 Non-HLA polymorphisms and autoimmunity
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To be activated the T cell needs to recognise the antigen by the TCR and a
costimulation. There are 2 main costimulatory molecules present in T cell activation, CD28
and CTLA-4. Those molecules are present in the surface of T cells and recognises the B7
molecule in antigen presenting cells. When CD28 binds B7, T cell stimulation and
progression occurs, on the other hand, when CTLA-4 binds B7 molecule, it promotes T cell
down regulation by competing to the B7 binding with CD28. CTLA-4 is also one of the
mechanisms used by T reg cells to suppress immunologic reactions. Polymorphisms may
cause CTLA-4 down regulation, and therefore elicit strong T cell activation and
inappropriate T reg activity, leading to autoimmunity (Hewagama and Richardson, 2009).
PTPN22 is a protein that regulates TCR and B cell receptor (BCR) signal transduction.
A polymorphism that replaces an arginine with a tryptophan at its encoding gene is
associated with interruption of PTPN22 binding in subsequent proteins in the TCR signal
cascade. This variation causes weak TCR and BCR signal, leading inefficient tolerance, this
therefore can predispose the individual to rheumatoid arthritis and type 1 diabetes
(Hewagama and Richardson, 2009).
NOD-like receptors is a big family of intracelular proteins. The most expressive proteins
of this family are NOD1 and NOD2. NOD1 is present in many tissues, whereas NOD2 is
expressed only in monocytes, granulocytes, dendritic cells and, in low quantities, in
lymphocytes. NOD2 protein is made of 3 main domains, a C-terminal domain (responsible
for microbial fragments recognition), a central domain (that is ATP regulated) and a N-
terminal domine (containing a caspase-recruiting domine (CARD)). NOD1 and NOD2
proteins recognises peptidoglycans from bacterial cell wall (presents in both gram positive and
gram negative bacterias). When NOD1 and NOD2 recognises bacterial structures in cell
cytoplasm, the N-terminal domine is exposed, thus the caspase domine became reactive
leading to a intracelular cascade that activates NF-kB, caspase-1 and MAPK. The
consequence is transcription of pro inflammatory proteins, growth and apoptotic factors.
(Antosz and Osiak, 2013)
There are polymorphisms characterised by weak NOD1 and NOD2 activation. The
NOD weakness can lead to unresponsiveness against harmful microbes. This microbes pierces
the epithelium initiating a inflammatory reaction, thereby causing inflammatory bowel
disease, since a large portion of the immune system cells are found in the gut, and it is an

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open system to external pathogens, this is one of the most affected regions. In the other hand,
some polymorphisms can lead strong NOD activation, thereby causing excessive production
of pro inflammatory diseases, thus eliciting tissue harsh like in Blau Syndrome. (Antosz and
Osiak, 2013)
Some self antigens are normally presented peripherally in the organism. In some
occasions those antigens can be erroneously expressed in thymus. This atypical situation can
generate responsiveness leading to an autoimmune disease. AIRE is a thymic protein that
regulates the expression of many self antigens and participates in the negative selection of
autorreactive T cells. Some AIRE polymorphisms may cause thymic expression of antigens
that is just normally expressed in periphery, thereby causing T cell responsiveness for that
antigen. Thymic insulin expression is correlated with AIRE polymorphisms and diabetes I.
The AIRE gene expression is regulated by the p38 MAPK protein, which positively interacts
with AIRE synthesis. Some disruptions in p38 MAPK pathway is related to myelomonocytic
leukaemia. The AIRE expression pathway in thymic cells is not well understood, but several
studies show its relation with periphery antigen expression in thymus (Sabater et al, 2005).
Antibody secretion in activated B cells is modulated by a feedback mechanism. The
secreted antibodies bind to a FC receptor located in the B cell triggering the inhibition. This
receptor related to B cell modulation is called FcgRIIB. Polymorphisms in this
immunomodulatoy receptor may cause poor B cell inhibition and are related to autoimmune
diseases like systemic lupus erythematosus (Hewagama and Richardson, 2009).
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Systemic lupus erythematosus
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Systemic lupus erythematosus (SLE) is an autoimmune disease and has many different
causes and clinical symptoms, among which, thrombocytopenia, haemolytic anemia, arthritis,
glomerulonephritis and skin rashes took part. The incidence is bigger in woman, due to
hormone influence. As a autoimmune systemic disease, the main characteristic is the
development of autoantibodies that act against cytoplasmic and nuclear proteins. The main
diagnostic test for SLE is the identification of antinuclear antibodies. This characteristic is
present in 70% of SLE patients. However, the disease can arise by the combination of many
other polymorphisms that affects the ability to promote self tolerance (Mok and Lau, 2003),
(Rahman and Isenberg, 2008).

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 When an individual carries a common polymorphism of SLE, it is not certain that SLE
will arise, however the chances are greater.
MHCII molecules are related to CD4+ T cell activation and CD4+ T cells participate
in both cell mediated and humoral immunity. As known, HLA-DR is one of MHCII protein
encoder. HLA-DR polymorphisms, HLA-DR3 and HLA-DR2, are related with production
of antibodies against self antigens in SLE (Rahman and Isenberg, 2008).
Some scientific observations provided new hypotheses for the SLE pathogenesis. One
hypotheses that exemplify the multifactorial nature of the disease states that: when a
individual is exposed to UV rays (specially UVB), keratinocytes undergo apoptosis. An
inadequate clearance of those cells promotes exposure of nucleic and cytoplasmic proteins,
this can happen when complement proteins and other cell receptors are faulty, thus leading to
defects in macrophage cell recognition and cleaning. When this nucleic exposure occurs in an
individual with polymorphisms of SLE susceptibility genes, the T and B cells self tolerance
mechanisms for this nucleic and cytoplasmic proteins may be ineffective. Thereby, non self
tolerant B cells can recognise self nuclear and cytoplasmic proteins and so start producing
and secreting antibodies against them. The process causes more cell lysis and nucleic proteins
exposure by antibody mediated reactions. The continuous self nucleic exposure result in high
affinity autoantibody production. When exposed to UV rays, the SLE patient can present
worse symptoms such as skin rashes (Mok and Lau, 2003).
Some clinical symptoms arises when antibodies produced against self antigens generate
imunocomplexes throughout the body, leading to local inflammation, and thereby, harming
tissues. Glomerulonephritis, arthritis and vasculitis are some of the symptoms (Rahman and
Isenberg, 2008).
Some of the treatment relies on B cell inhibition by administration of specific antibodies
for the B cell growth factor BAFF. Some immunosuppressants with systemic action like
azathioprine, mycophenolate mofetil and cyclophosphamide are employed (Faifax et al, 2012).
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Type I diabetes
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Type I diabetes is characterised by faulty production of insulin by beta cells of the
Langerhans islets in pancreas. The faulty production is due to an autoimmune disease
towards Beta cells. The disease is being increasingly common during childhood. Some studies
show that this incidence increase just in low age groups is not likely to be due to genetic
changes, they point to a increased environmental pressure on polymorphic genotypes

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favourable for diabetes I. It has been difficult to stabilise those environmental factors, the most
promising ones rely in viruses and microorganisms infections (Gillespie, 2006).
The immune response against self beta cells can occur by different ways. Macrophages,
CD4+ and CD8+ T cells can infiltrate the pancreatic islets promoting intense destruction. B
cells can produce antibodies against beta cells, those antibodies can be detected in serum
sample of the patient. The susceptibility for the development of the autoimmune mechanisms
is assigned to certain polymorphic genes (Gillespie, 2006).
The reaction against beta cells is mediated by 3 main antigens: glutamic acid
decarboxylase (GAD 65),a protein tyrosine phosphatase-like (IA-2) and insulin. 90% of
people diagnosed with type I diabetes express autoantibodies against those antigens. If those
antibodies are detected in a normal patient it does not mean presence of the disease, but this
can predict high risk for its development (Gillespie, 2006).
The polymorphisms of HLA gene, HLA-DR4-DQ8 and HLA-DR3-DQ2, were found
in 90% of children submitted in a type I diabetes study. Some studies show a correlation
between CTLA-4 gene and insuline gene, in chromosome II, as supporting the type I diabetes
occurrence. The previous addressed topics showed the relation between CTLA-4 and HLA
genes with other autoimmune diseases, this reiterates the fact that similar faulty biological
pathways can lead to different diseases (Gillespie, 2006).
Some therapeutic strategies are being held focusing on tolerance induction to the most
common antigens countered by the immune system. Some treatment are based on
Langerhans islets transplant in the liver of diabetes I patients together with
immunosuppressants. Insulin administration remains the main palliative care for the disease.
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Conclusion
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The pathogenesis of many types of autoimmune diseases remains unclear. It is very
intriguing to observe that a disease can arise from many different factors, much of which we
have no control over. Studies are been held in order to clarify the main pathways and
influences involved in the development of immune response against self antigens. The mais
objective is to promote increasingly better treatments, and thereby giving better quality of life
to many people.
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References
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Animesh and LOPEZ
Autoimmune Diseases: The Failure of Self Tolerance
In-text: (Animesh and LOPEZ, 1990)
Bibliography: Animesh, and LOPEZ, (1990). Autoimmune Diseases: The Failure of Self
Tolerance.

Antosz, H. and Osiak, M.

NOD1 and NOD2 receptors: integral members of the innate and adaptive immunity system
In-text: (Antosz and Osiak, 2013)
Bibliography: Antosz, H. and Osiak, M. (2013). NOD1 and NOD2 receptors: integral
members of the innate and adaptive immunity system.

Gillespie, K.
Type 1 diabetes: pathogenesis and prevention
In-text: (Gillespie, 2006)
Bibliography: Gillespie, K. (2006). Type 1 diabetes: pathogenesis and prevention.

Hewagama, A. and Richardson, B.
The genetics and epigenetics of autoimmune diseases
In-text: (Hewagama and Richardson, 2009)
Bibliography: Hewagama, A. and Richardson, B. (2009). The genetics and epigenetics of
autoimmune diseases.

Mok, C. C. and Lau, C. S.
Pathogenesis of systemic lupus erythematosus
In-text: (Mok and Lau, 2003)
Bibliography: Mok, C. and Lau, C. (2003). Pathogenesis of systemic lupus erythematosus.
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Rahman, A. and Isenberg, D.
Systemic Lupus Erythematosus
In-text: (Rahman and Isenberg, 2008)
Bibliography: Rahman, A. and Isenberg, D. (2008). Systemic Lupus Erythematosus. [online]
Nejm.org. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMra071297 [Accessed
18 Aug. 2014].

Sabater et al, L.
Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin
expression in the thymus
In-text: (Sabater et al, 2005)
Bibliography: Sabater et al, L. (2005). Insulin alleles and autoimmune regulator (AIRE) gene
expression both influence insulin expression in the thymus.

Faifax et al
BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus
In-text: (Faifax et al, 2012)
Bibliography: Faifax et al, (2012). BAFF/BLyS inhibitors: A new prospect for
treatment of systemic lupus erythematosus.

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