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Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18 Page 281

The PD-1/PDL-1 axis has been investigated in the peripheral blood and the infiltrating lymphocytes in
glands of patients with GD and compared with non-multinodular goitres as non-autoimmune controls
[27]
and healthy controls (HC) . A decrease of naïve as well as an increase of memory and effector subsets
[27]
of CD4 T cells was observed in GD as compared with the healthy donors (HD) . Besides, infiltrating
lymphocytes in the gland of GD patients were predominantly effector and memory cells. PD-1 was found
higher in GD than HD in CD4 T cells, and it increased in effector memory T cells re-expressing CD45RA
(TEMRA), effector and central memory subsets. PD-1 expression increased in infiltrating CD4 and CD8 T
cells in infiltrating lymphocytes with predominance on effector and memory subsets. The expression of
PDL-1 but not programmed death ligand 2 (PDL-2) was observed in epithelial thyroid follicular cells in
the thyroid tissue from GD patients but not in non-multinodular goitres patients .
[27]
Rheumatoid arthritis (RA) is a chronic progressive inflammatory disorder characterised by damage of
articular cartilage and joint destruction [28-31] . Environmental, genetic, infectious and hormonal factors can
contribute to the pathogenesis of the disease [32,33] . The overproduction of TNFa generates inflammation
[34]
and damages the joints. The interaction of B and T lymphocytes with synovial-like fibroblasts and
macrophages causes the overproduction of TNFa that induces the production of several inflammatory
cytokines, such as interleukin-6 (IL-6) [35,36] . Several animal and clinical studies revealed the presence of
CD4 T cells in the perivascular cuff and infiltration of CD8 T cells into the tissue. Depletion of T cells or
treatment of anti-cytokines that are involved in T-cell activation or promote antigen-presentation reduces
inflammation. T helper 17 cells are the primary T cell subsets involved in inflammation and autoimmunity
[37]
-/-
in RA . PD-1 C57BL/6 mice developed arthritis. PD-1 polymorphisms have been reported to be
associated with RA [38,39] . Expression of PD-1 was detected in synovial T cells and macrophages in patients
[40]
with RA . In the peripheral blood of RA patients, PD-1 was significantly decreased in CD4 T cells (P =
[41]
0.002) and CD8 T cells (P < 0.001) as compared with HC (P < 0.05) . DAS28 score is a measure of disease
[41]
activity in RA, and PD-1 expression was found inversely correlated with DAS28 scores in RA patients .
Besides, CRP is an indicator of inflammation and cases with positive CRP detection had a lower proportion
+
+
[42]
of PD-1 CD4 T cells than those with negative CRP .
Systemic Lupus Erythematous (SLE) is an autoimmune disease generated by the production of antibodies
against self-antigens and deposition of immune complexes in different tissues. Inflammation and
[43]
multisystem disorders characterise the disease . The disorder affects mainly women of reproductive
age with an incidence of 20-70 cases per 100,000 individuals [44,45] . Environmental, genetic and hormonal
factors are relevant in the pathogenesis of the disease [46-48] . Genetic variations in the immune checkpoint
genes such as PD-1, T-cell immunoglobulin domain, mucin domain (TIM) and CTLA-4 increase the
susceptibility to develop the autoimmune disease as a consequence of the breakdown of immune tolerance
to self-antigens [49,50] . Several single-nucleotide polymorphisms (SNPs) have been identified to affect PD-1
function and to contribute to tumours and autoimmune disease [49,50] . The frequencies of PD-1 SNPs (PD1.1,
PD1.3, PD1.5 and PD1.9) were analysed in SLE patients. The PD1.5 genotype frequency was increased in
Iranian, Malaysian and European patients with SLE as compared with healthy donors [51-53] . The distribution
of PD1.5 C/C, PD1.5 C/T and PD1.5 T/T genotypes versus other genotypes in patients with SLE differed
[53]
from healthy controls . In addition, there were significant differences in the PD1.5 genotypes between
patients with renal involvement and neurological involvement and between neurological involvement and
[53]
HC . The allelic analysis revealed that there was a significant association between PD1.5 allele frequency
and SLE susceptibility .
[53]
Type I diabetes (TID) is caused by autoreactive cells that destroy the insulin-producing beta cells in the
[54]
pancreatic islet of Langerhans . PD-1 and PDL-1 protect from TID. PD-1 deficiency accelerates the
onset and the frequency of TID in NOD (non-obese diabetic) mice and infiltration of T cells into the
islets. PD-1 or PDL-1 but not PDL-2 blockage rapidly induces diabetes in NOD mice with an expansion