Systemic lupus erythematosus and rheumatoid arthritis

9. Candidate genes involved in immune functions 
For this study, candidate genes were chosen based on their involvement in 
immune functions. SNPs of the oestrogen receptor-
α
gene (
ESR1
), the 
programmed cell-death 1 gene (
PDCD1)
, and the protein tyrosine phosphatase 
non-receptor type 22 gene (
PTPN22
) were analysed for a relationship with SLE 
and RA.
Oestrogens are mainly produced in ovary and testis but are also produced 
through aromatisation of androgens in peripheral tissues and in adrenal glands. 
The effects of oestrogens are mediated through oestrogen receptors, which are 
ligand activated transcription factors with the same characteristics and 
functional properties as nuclear receptors.
135
Oestrogens are known to stimulate 
B-cell growth, antibody production, and cytokine release, all of which could 
contribute to an increased risk of susceptibility to develop SLE.
136-138
However, 
experiments 
in vivo
in mice have shown a dual role for oestrogen in the immune 
response: suppression of inflammation and stimulation of antibody production. 
Oestrogen has been shown to mediate a down-regulation of granulocyte 
induced inflammation, T-lymphocyte dependent delayed-type hypersensitivity, 
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and natural killer cell activity, and an up-regulation of antigen-specific antibody 
responses and polyclonal Ig production.
139
There are two kinds of oestrogen receptors: oestrogen receptor-
α
(OR
α
) and 
oestrogen receptor-
β
(OR
β
). OR
α
is present in various tissues including those of 
the female and male reproductive tract, the female mammary gland, bone, the 
cardiovascular system and regions of the brain. 
140
Analysis of peripheral blood 
mononuclear cells from patients with SLE has shown increased levels of OR
α
mRNA expression compared with healthy controls.
141
Deficiency of OR
α
in 
lupus prone strains of mice significantly prolonged survival, reduced 
proteinuria, and reduced the renal pathology score, compared with wild-type 
mice.
142
These positive effects associated with deficiency in OR
α
were only 
seen in female mice but did not affect the titres of anti-dsDNA levels in the 
lupus prone mice. A deficiency in the OR
β
had no effect on disease in either the 
wild-type or lupus prone strain or sex.
142
Polymorphisms of the
 ESR1
gene have been widely studied and associations 
have been made with a number of complex traits such as myocardial 
infarction,
143
cognitive impairment,
144
breast cancer,
145
Alzheimer’s disease,
146
osteoporosis,
147
rheumatoid arthritis,
148
and lupus nephritis.
149
The two main 
polymorphisms studied in those association studies were 
PvuII
(rs2234693) and 
XbaI
(rs9340799), both located within the first intron of the 
ESR1
gene.
The programmed cell death 1 gene
 
(
PDCD1
)
is one of the most widely 
recognized candidate genes for SLE. An intronic risk allele, the 
PD1.3
A allele, 
has been associated with SLE susceptibility in different populations.
150-152
In a 
recent meta-analysis, the 
PD1.3A
allele was confirmed to be associated with 
SLE among individuals of non-Spanish European descent.
153
PDCD1
encodes 
for the programmed death 1 (PD-1) receptor, which is a member of the 
CD28/CTLA4 family of T-cell regulators 
154
expressed on the cell surface of 
activated T- and B-cells.
155
PD-1 interacts with its two ligands, PD-L1 and PD-
L2, which are expressed on various tissues of the immune system.
156
Signalling 
through PD-1 produces a negative response in T-cell function leading to a 
suppression of IFN-
γ
production, proliferation of T-cells, and increased T-cell 
apoptosis.
157; 158
PD-1 has been found, using immuno-histochemical techniques, 
within the glomeruli and renal tubules of renal biopsies from patients with lupus 
nephritis but not those from control patients.
159
One of the ligands, PD-L1, has 
been found on renal tubules of renal samples from either patients with lupus 
nephritis or controls.
159
The 
pdcd1
gene has been knocked out in mice giving 
rise to a phenotype resembling SLE with arthritis and glomerulonephritis.
160
Lupus nephritis is a common and severe manifestation of human SLE and the 
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PD1.3
polymorphism has been shown to be associated with lupus nephritis in 
female patients with SLE.
161
The gene protein tyrosine phosphatase non-receptor type 22 (
PTPN22
) encodes 
for the lymphoid protein tyrosine phosphatase (Lyp), which has shown to be 
involved in the control of T-cell activation through studies of an animal model 
and human cell lines.
119; 162
A missense SNP in position 1858 (rs2476601), also 
known as R620W, was first found to be associated with type I diabetes
163
. 
Currently it is the strongest candidate gene outside the HLA region for 
autoimmunity and has been associated with a number of autoimmune diseases 
including systemic lupus erythematosus
164; 165
, Graves’ disease
166-168
, Hashimoto 
thyroiditis
169
, generalized vitiligo
170
, myasthenia gravis
171
, systemic sclerosis
172
, 
Addison’s disease
173
, alopecia areata
174
, juvenile idiopathic arthritis
175
, and 
rheumatoid arthritis.
119; 169; 175-179
The strongest associations with RA, generally 
accepted today, had been found in patients with sero-positive diseases.
180
In 
autoimmune diseases with little or no auto-antibody production, 
e.g.
, multiple 
sclerosis (MS)
181; 182
and Crohn’s disease (CD)
183
, no associations have been 
found with 
PTPN22
. The Lyp protein is expressed in different cell types, 
i.e.
, T-
cells, B-cells, monocytes, neutrophils, dendritic cells and natural killer cells.
119
The 
PTPN22
1858T allele changes codon 620 from an arginine residue to a 
tryptophan. This amino acid substitution disrupts the binding of Lyp to an 
intracellular kinase, Csk, which can no longer inactivate the Src family of 
kinases, Lck and Fyn, involved in T-cell activation.
184-186
The result of this 
missense mutation is a possible loss of negative regulation of T-cell 
signalling.
119; 163
One functional study on the role of the 1858 T allele in T-cell 
activation has been performed in type I diabetes showing that the risk allele 
made Lyp a more potent negative regulator of T-cell activation.
187
Studies have 
also shown that homozygosity for the risk allele results in a deficient of T-cell 
responsiveness upon antigen stimulation whereas heterozygosity results in 
reduced responsiveness of CD4+ memory cells with diminished calcium 
mobilization, CD25 expression and IL-10 production upon TCR stimulation.
188
However, the functional implications of positivity for the 1858T allele is not 
restricted to the T-cell compartment. B-cell signalling is impaired in individuals 
carrying the risk variant, characterized by deficits in proliferation and a 
decreased phosphorylation of important signalling proteins.
189