INTRODUCTION:

Physical barriers, such as the gastrointestinal and respiratory tracts and skin, and soluble mediators, like antimicrobial substances and defensins, provide primary defences by keeping pathogens out of the body ¹. Autoimmune disorders are a heterogeneous group of diseases believed to arise from immune-mediated attack against self-antigens. In most instances, the events that initiate the immune response to self-molecules are unknown. But a number of studies suggest associations with environmental and genetic factors and certain types of infections.

Some common autoimmune diseases are rheumatoid arthritis, multiple sclerosis, diabetes, cardiomyopathy, antiphospholipid syndrome, myasthenia gravis, Crohn’s disease, Graves ’ disease, psoriasis and alopecia.

Psoriasis is a common, chronic inflammatory skin disease, characterized by T cell-mediated hyper-proliferation of keratinocytes, affecting about 2% of the worldwide population ². It is mostly inherited and mainly characterized by sharply marginated scaly, erythematous plaques that develop in a relatively symmetrical distribution. The most commonly affected sites are the scalp, tips of fingers and toes, palms, soles, umbilicus, gluteus, under the breasts and genitals, elbows, knees, shins and sacrum ³. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Psoriasis is linked to dandruff and to some forms of arthritis. In recent years, substantial advances have been made in elucidating the molecular mechanisms of psoriasis. However, major issues remain unresolved, including the primary nature of the disease as an epithelial or immunologic disorder, the autoimmune cause of the inflammatory process ³.

Psoriasis is associated with a high degree of morbidity; patients are embarrassed about the appearance of their skin, and there are side effects of medications. Its prevalence is equal in men and women and can first appear at any age, from infancy to elderly, although the mean age of development has suggested being around 30 years old ⁴. Psoriasis affects people of all ages, but there is a strong tendency for disease onset in early adulthood in patients who develop psoriasis due to genetic transmission ⁵. Researches show that whether a person develops psoriasis or not may depend on a “trigger‟. Possible psoriasis triggers include emotional stress, skin injury, systemic infections, certain medications and intestinal upsets. The success of translational research in psoriasis is probably best illustrated by the US Food and Drug Administration’s (FDA’s) approval of alefacept and efalizumab in 2003 ⁴.

Many new findings on T cells and their contributions to the disease development have challenged our conventional views regarding psoriasis as a T helper (Th) 1-mediated skin disease and prompted us to reassess T-cell functions in psoriasis ² . Several psoriasis associated chromosomal regions (PSORS 1–10) have been identified by conventional family-associated on genetic linkage approach, with PSORS 1, tightly linked to HLA-Cw6 as the most frequent detected allele ⁶.

Central tolerance mechanisms result in deletion of the majority of self-reactive T lymphocytes, some T cells specific for self-antigens escape into the periphery. The immune system has developed multiple mechanisms to prevent harmful activation of immune cells. One such mechanism is the balance between co-stimulatory and co-inhibitory signals delivered to T cells. Some co-stimulatory interactions potentiate the activation and proliferation of naive T cells, while others inhibit T cell activation and promote regulation. The B7-1 (CD80)/B7-2 (CD86)- CTLA-4 pathway is the best-characterized inhibitory pathway for T-cell activation (Watanabe, Nakajima, 2012). Another inhibitory pathway involves programmed death-1 (PD-1), which interacts with PD-L1 (B7-H1) and PD-L2 (B7-DC) and negatively regulates T cell activation⁷. PD1:PD-L interactions maintain peripheral tolerance and are exploited by tumors and viruses that cause chronic infection to evade immune eradication. This pathway has emerged as a potential therapeutic target for either enhancing or dampening the immune response ⁸. In this review we shall summarize our current understanding of the immunoregulatory functions of the PD-1:PD-L pathway and its possible role in autoimmune disorders.

Regulation of PD-1 and its Ligands:

PD-1 is a 50–55 kDa type I transmembrane glycoprotein composed of an IgV domain sharing 21–33% sequence identity with CTLA-4, CD28, and inducible co-stimulatory molecule ⁹. The ligands of PD-1 (PD-L1 and PD-L2, PDLs) are type I transmembrane glycoprotein composed of IgC and IgV domains. The amino acid identity between PD-L1 and PD-L2 is about 40%, while the amino acid identity between PD-Ls and B7s is about 20%.Programmed death-1 (PD-1) is a 288 amino acid protein expressed in B and T cells as well as myeloid-derived cells ¹⁰. In 1992, programmed cell death-1 (PD-1) was identified as a molecule whose expression was strongly induced upon apoptotic stimuli¹¹. PD-1 expression was first discovered on dying cells, but unlike its name, it doesn’t trigger cell death, but rather anergy by triggering inhibitory signals into the cell ^{11, 12}. PD-1 is an immunoglobulin (Ig) superfamily member that has an N-terminal IgV-like domain, an approximately 20 amino acid stalk separating the IgV-like domain from the plasma membrane, a transmembrane domain, and a cytoplasmic domain with an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immune-receptor tyrosine-based switch motif (ITSM). Mutagenesis studies indicate that the tyrosine within the ITSM motif is essential for PD-1 function in T cells and B cells ¹³ . Signaling through PD-1 is triggered by engagement with its known ligands, PD-L1 and PDL2. The binding of either PD-L1 or PD-L2 to PD-1 results in the recruitment of SH2-domain containing tyrosine phosphatase-1 (SHP-1) and SHP-2 on to the PD-1 cytoplasmic tail. The subsequent signaling inhibits positive signaling pathways and results in T-cell anergy ¹⁴. PD-1 signaling dephosphorylates proximal signaling molecules and augments PTEN expression, inhibiting PI3K and AKT activation⁸. The consequences include decreased T-cell proliferation, cytokine production and cell survival. Of the PD-1 ligands, PD-L1 has very broad expression, whereas PD-L2 is inducibly expressed in a more restricted fashion. PD-L1 is expressed constitutively on murine T and B cells, DCs, macrophages, mesenchymal stem cells and bone marrow-derived mast cells but not mouse, vascular endothelial cells and T cells ¹².

Unlike the classic B7 family members, B7-1 and B7-2, which are mainly restricted to expression on APCs, PD-L1 is expressed in a number of non-hematopoietic tissues including the heart, pancreas, placenta, vascular endothelium, liver, lung, and skin¹⁵. Interferon-gamma potently up regulates PDL1, and to a lesser extent PD-L2. IL-4 and GMCSF are the strongest known stimuli for inducing PD-L2 expression. In addition to binding PD-1, PD-L1 can also bind the B7–1 (CD80) molecule, thus connecting the PD-1:PD-L1 pathway with the B7–1:CD28/CTLA-4 pathway⁸. IL-2 can trigger Akt activation through STAT5 and circumvent PD-1 mediated inhibition of Akt activation. Although CTLA-4 also blocks Akt activation, it does not interfere with PI3K activity but instead blocks Akt phosphorylation by activation of protein phosphatase 2 (PP2A)¹³. The comparison of the gene expression profiling of T cells exposed to anti-CTLA4 vs anti-PD-1 Ab revealed that PD-1 has a more pronounced inhibitory activity (90% vs.67% inhibition of gene products up regulated through the combined addition of anti-CD3 and anti-CD28 antibodies) ¹⁶. It was also recently shown that PD-1 signaling influences the metabolism of T cells. PD-1 signaling results in the inhibition of glycolysis and metabolism of amino acids while simultaneously promoting fatty acid oxidation ¹⁷.

Recently, the crystal structures of PD-1 and PD-Ls were clarified. In contrast to CTLA-4 that uses a hydrophobic sequence, MYPPY, in the loop connecting F and G b-strands of its IgV domain to bind B7-1 and B7-2, PD-1 uses its front b-face (AGFCC0 b-strands) to bind to the b-face of PD-L1 (AGFCC0) or PD-L2 (AGFC). This face-to-face interaction of PD-1 and PD-Ls makes the contact area (1, 870 A°²) larger than that of CTLA-4 and B7s (~1, 200 A°²) and makes the PD-1/PD-Ls complex more compact (76 A° and 100 A° for PD-1/PD-Ls and B7-1/CTLA-4, respectively) ¹³. The structure of PD-1 and PD-Ls showed high similarity to those of T-cell receptor (TCR) antibody and CD8 dimer ¹⁰. The crystal structure determined earlier demonstrates that the receptor-ligand interaction is mediated in its major part by residues of C⁰CFG strands within both PD-1 and PD-L1. The protein-protein contacts involve both hydrophobic interactions and polar interactions and bury a total surface area of 1, 970 A°² ¹⁸. With the help of mutagenesis studies and nuclear magnetic resonance (NMR) data have suggested that the overall binding mode of hPD-1 and hPD-L1 is consistent with that of mouse-derived receptor and a human-derived ligand. However Zak et al (2015) reported the crystal structure of the human PD-1/human PD-L1 complex, which indeed documents significant differences in the binding between murine and human PD-1 and the ligand (hPD-L1).

By using the approach of fragment-based lead design has become an important and powerful approach in structure-based lead discovery. Zak et al reported the hPD-1 interaction surface of hPD-L1 through three major hot spots, two of which are expected to form a druggable pharmacophore. The first is a classical pocket of mostly hydrophobic character accommodating Ile134. This pocket is composed of the side chains of LTyr56, LGlu58, LArg113, LMet115, and LTyr123, and is of perfect size and properties to accommodate a six membered aromatic ring. The second hot spot is located just nearby and accommodates Ile126. It is composed of LMet115, LAla121, and LTyr123, and could likely be effectively filled by a branched aliphatic moiety. The third hot spot is an extended groove accommodating Tyr68, Gln75, and Thr76. It is formed by the main chain and the side chains spanning residues LAsp122 to LArg125, and is flanked by the side chain of LAsp26 ¹⁸.

PD-1 and its ligands in autoimmunity:

Involvement of PD-1 in autoimmunity was first demonstrated by the autoimmune phenotype of PD-1-deficient mice¹⁹. PD-1-deficient mice develop spontaneous autoimmune diseases including SLE, nephritis cardiomyopathy in Balb/c mice, gastritis, sub-acute type I diabetes, and lethal myocarditis, indicating an essential function of PD-1 in the mechanisms of tolerance²⁰. Significant depositions of IgG3 and C3 are detectable in the glomeruli of C57BL/6-Pdcd1^-/-mice. In addition, most of the C57BL/6-Pdcd1^-/-mice develop arthritis¹⁹. Based on these animal experiments, single-nucleotide polymorphisms (SNPs) on human PD-1 gene >30 SNPs have been identified. Prokunina et al. reported that the allele A of a SNP named PD1.3 (PD1.3A) in intron 4 is associated with the development of SLE. The PD1.3 locates on the binding site for the runt related transcription factor 1 (RUNX1) and PD1.3A interferes the binding of RUNX1 resulting in the impaired induction of PD-1 ²¹. PD-1 expression on tissue has also been shown to be crucial to promoting peripheral tolerance. Likewise, PD-L1 expression on non-lymphoid cells as well as APCs has been demonstrated to be important in the negative regulation of T cells.

Type 1 diabetes (T1D) is an autoimmune disease Diabetes develops in NOD mice at 14 to 30 weeks of age. Several studies have shown either reduced regulatory T cells (Treg) numbers or altered Treg function in human T1D. Tregs utilize a number of different mechanisms to inhibit immune responses, including secretion of anti-inflammatory cytokines ¹³. At 10 wk of age, in male NOD mice that rarely develop overt diabetes, PD-1–PD-L1 blockade had a similar effect to that seen in female NOD mice of the same age, with an 80% incidence of diabetes after anti–PD-1 and 100% after anti–PD-L1 mAb treatment, indicating that the effect observed in NOD mice is not due to nonspecific islet cell toxicity but related to mAb treatment. There is PD-L1 expression in the inflamed islets of Langerhans, suggesting a novel mechanism of down-regulating lymphocyte function at the site of inflammation by parenchymal cells. Pathologically, there was marked destructive insulitis in the young diabetic animals after eitherCTLA-4, PD-1, or PD-L1 blockade, whereas the control animals had minimal inflammation of the islets ²². PD-L1 not only is found on the islets but is also expressed on the vascular endothelium in the pancreas ²³. Endothelial expressed PD-L1 protects from cytolysis but may also act as a final checkpoint before diabetogenic T cells enter the tissue. Endothelial expression of PD-L1 may drive iTreg development using in vitro allograft models. TGF-β has been shown to be important in regulating T1D in the NOD mouse. Tregs cannot control disease progression in TGFβRII knockout NOD mice, possibly due to the lack of Treg presentation of surface-bound TGF-β to effector T cells. Although the exact function of PD-1 signaling on Treg function in T1D is still unclear, it is possible that PD-1 modulation may change contact time as well as the local cytokine milieu ¹³. Figure 1:- represent the ligand–receptor interactions between T cells and antigen-presenting cells (APCs).

MS is an autoimmune disease in which immune-mediated attack of the brain and spinal cord results in inflammation and demyelination of the central nervous system (CNS). Adoptive transfer of CD4+CD25+ Tregs decreased inflammation of the CNS and conferred substantial protection from clinical EAE. Expression of PD-1 and PDL-1 in the CNS is primarily up-regulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice²⁴ The expression of PD-1 is significantly increased on myelin basic protein (MBP)-stimulated CD4+ and CD8+ T lymphocytes isolated from the peripheral blood of patients with stable MS compared to lymphocytes from patients with acute remissions and relapses²⁵. PD-L2 on microglial and CNS infiltrating APCs has been shown to be less potent than PD-L1 in the regulation of cytokine (IFN-γ, IL-17, etc.) production and the activation of auto-reactive T-cells²⁶. IL-12, a cytokine mainly produced by APCs, is also shown to suppress the development of EAE through stimulating IFN-γ production in APCs and enhancing downstream PD-1/PD-L1 signaling²⁷.

The pathological hallmarks of AD are the extracellular accumulation of amyloid plaques and intracellular deposition of neurofibrillary tangles ²⁸. Expression of PD-1 on CD4+ T-cells and PD-L1 on CD14+ monocytes/macrophage significantly decrease in AD patients and patients with mild cognitive impairment (MCI) ²⁵. Torres et al reported that although the IL-10 serum levels are comparable in AD patients and healthy controls, the frequency of CD4+ T-cells expressing IL-10 in AD group is much higher than that in controls, indication a systemic effort to counterbalance the pro-inflammatory responses in the AD brain²⁹.The number of PD-1+ Tregs is increased both in patients with fully developed AD and with MCI. Neurons express PD-L1 and PD-L2 upon inflammation and produce TGF-β is intriguing in light of evidence describing that encephalitogenic T cells are converted to iTregs upon neuronal encounter³⁰.

The concept of cancer immuno-surveillance was first proposed in 1909 by Ehrlich who suggested that evolving tumors are constantly identified and eradicated by the host immune system even before clinical manifestations occur. Several preclinical reports also showed that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Additionally, PD-L1 is expressed on various human cancers, including urothelial cancers, gastrointestinal cancers, lung cancer, breast cancer, melanoma, and ovarian cancer, as well as on tumor-infiltrating immune cells in the tumor microenvironment³¹. There is an immense level of interest and investment by pharmaceutical companies in the PD-1/PD-L1 pathway. Several major companies have entered the fray, with multiple phase III registration trials already underway in a variety of malignancies, most notably melanoma, RCC, and NSCLC³². Considering the importance and relevance of PD-1 and PD-L1/2 in tumor malignancies and patient survival, it has been hypothesized that PD-1 or PD-L1/2 blockade may provide a promising immunotherapy for patients with cancer³³. This is supported by the positive preclinical data. The principle of PD-1/PD-L1 blockade in clinical trials is developing humanized antibodies or human IgG to bind either PD-1 or PD-L1, thereby blocking the ligation of PD-1 and PD-L1 and the downstream inhibitory signaling events ³⁴. Blockade of PD-L1 may cause less side effects and toxicity as PD-L2 can serve as an alternate ligand for PD-1 ³³. Treatment with nivolumab, an anti–PD-1 mAb in combination with ipilimumab (anti–CTLA-4) for patients with melanoma has resulted in up to 65% of patients developing an uncharacterized skin rash, depending on the dosing of the two agents.

PD-1 and its ligand, PD-L1, are involved in controlling contact dermatitis ¹². Kim et al (2015) reported that impaired function of Tregs in psoriasis could be a reason for decreased expressions of PD-L1, 2 of psoriatic epidermis. PD-L1 of keratinocytes would also have significant importance in the pathogenesis of psoriasis. T cells migrate into skin and express cytokines such as IL-22 and IL-17A, which play critical roles in development of PsD induced by IL-23 and imiquimod. GDL T cells are the major producers of IL-17A and IL-22 in the psoriatic epidermis. PD-1 expressed on GDL T cells directly suppresses the production of proinflammatory cytokines such as IL-17A, which is a critical driver of psoriasiform inflammation in mice and humans. Mice treated with anti–PD-1 mAb developed enhanced ear swelling compared with mice treated with isotype Abs. Imai et al 2015 also reported that quantitative histological analysis revealed an ∼2-fold increase in epidermal thickness in the PD-1KO mice compared with WT mice and the epidermis of PD-1KO mice accumulated ∼20-fold more surface area composed of neutrophilic abscess. Levels of IL-17A and IL-22 were enhanced in the PD-1KO mice after application of IMQ. IL-22 has been linked to epidermal acanthosis ^{35, 36}. PD-1 expressed on GDL T cells directly suppresses the production of proinflammatory cytokines such as IL-17A, which is a critical driver of psoriasiform inflammation in mice and humans ³⁵.

CONCLUSION:

Interactions between PD-1 and its ligands play a variety of roles in T cell activation and the maintenance of immune homeostasis. PD-1 is expressed on activated T as well as B cells. The expression of PD-L1 in nonlymphoid tissues regulates autoreactive lymphocytes at sites of inflammation. In the recent years much is known about the PD-1/PD-L1 pathway in tumor immunity. The research on oncology has provided a new wide space for autoimmune disease treatment though PD-1/PD-L1 pathway as a promising new therapeutic opportunity. Small molecules as agonists and antagonists targeting PD-1/PD-L1 pathways can be instrumental in treating a wide range of autoimmune conditions and cancer.

CONFLICT OF INTEREST STATEMENT:

There is no conflict of interest between the authors.

ACKNOWLEDGEMENT:

The authors sincerely thank VIT University, Vellore and its management team for providing all the necessary resources and facilities required for conducting this entire study.

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Received on 27.06.2017 Modified on 28.07.2017

Research J. Pharm. and Tech. 2017; 10(8): 2771-2776.

DOI: 10.5958/0974-360X.2017.00491.7