Abstract

Cosentyx is an IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17A receptor. IL-17A is a cytokine that is involved in normal inflammatory immune response. IL-17A is secreted by memory CD4+ T cells, and Th 17 helper cells in defense against fungi, extracellular bacteria, and Mycobacterium tuberculosis. IL-17A acts on IL-17 receptor A (IL-17RA) and C (IL-17RC). IL-17A is  produced by oligodendrocytes, astrocytes, dendritic cells, keratinocytes, and mast cells. The overall structure of IL-17A adopts cystine knot fold. IL-17A activates nuclear factor-κB (NF-κB), a transcription factor associated with inflammation, and p50 and p65, which are components of the classical NF-κB pathway. Also, IL-17A induces the expression of IκBζ, which is a positive regulator of transcription by the TLR and IL-1R pathways. Interleukin-17A play roles in human disease pathogenesis based on the presence of IL-17A in the skin and/or joints of patients with immune-mediated diseases such as psoriasis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), and MS. The role of Th 17 cells and their effectors in host defense suggests that IL-17A inhibition could increase the risk of serious infection and various immune-mediated disorders. To eliminate these side effects, future studies should focus on the role of the inhibition of IL-17A and IL-17F together, as it is known from previous studies that IL-17A and IL-17F both are produced by Th 17 cells along with other cytokines in response to APC. Moreover, possible therapeutic targets could be IL-RA and IL-RC receptors, suppressing one of the receptors and not the other could lead to balanced amount of IL-17A in the body which would possibly not manifest severe side effects.

1 | History

Secukinumab (Cosentyx) was discovered and developed by Novartis using developmental name AIN457, and the first publication was a Phase I trial published in 2010 (90).

In January 2015, the FDA approved secukinumab to treat adults with moderate-to-severe plaque psoriasis (91).  It was the first IL17A inhibiting drug ever approved (92). In January 2016, the FDA approved it to treat adults with ankylosing spondylitis, and psoriatic arthritis and in February 2018 a label update was approved to include the moderate to severe scalp psoriasis.

2 | Genetics

Cosentyx is an IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17A receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Cosentyx inhibits the release of proinflammatory cytokines and chemokines(1). An inflammatory cytokine is a signaling molecule that is secreted from the immune cells and certain other types of cells to promote inflammation. Inflammatory cytokines are predominantly produced by T helper cells (Th) and macrophages and involved in the upregulation of inflammatory reactions (2). The cells also known as CD4 cells release cytokines to promote activity of other immune cells in adaptive immunity,and macrophages are the white blood cells that engulf debris or any foreign substances (11).  In one study, the analysis of the cDNA encoding murine interleukin (IL) 17(cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame of Herpesvirus saimiri. They reported that upon the cloning of human IL-17 (hIL-17), the human counterpart of murine IL-17. hIL-17 is a glycoprotein of 155 amino acids secreted as a homodimer by activated memory CD4+ T cells, which are activated by transforming growth factor–β (TGF-β) and IL-6 (3,5). Moreover, Interleukin-17 cytokine derived from a third class of helper T cells which are known as T cells type 17 (Th 17), and are essential for the defense against certain fungi, extracellular bacteria, and Mycobacterium tuberculosis. Defective control of Th17 cells and production of interleukin-17 are prominent in chronic inflammation and several immunoinflammatory disorders (4). This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO) (19). IL-17RA identified as a mammalian counter structure for HVS13 and subsequently shown to bind IL-17 with high affinity (13). Interleukin 17A (IL-17A) and Interleukin 17F (IL-17F) are two IL-17 family members that are secreted by Th17 cells and share the same receptors, IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC) (12). IL-17A contributes to pathogenesis of psoriasis (skin disease, non-infections uveitis, and rheumatoid arthritis (RA) (20).

2 | Expression

IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biological activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. IL-17RA and IL-17RC are ubiquitously expressed, including in keratinocytes, macrophages, fibroblasts, osteoblasts, and epithelial, endothelial, and dendritic cells (6). The study indicated that the lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of a required secondary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biological activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, which indicates an interaction between the expanded family of IL-17 ligands and their receptors (6). Expression of IL-17 has also been noted in the mRNA and protein in perivascular lymphocytes as well as in astrocytes and oligodendrocytes located in the active areas of Multiple sclerosis (MS) lesions (7). Furthermore, another study demonstrated that mast cells produce RORC-dependent IL-17A upon stimulation with TNF-α, IgG complexes, C5a, and LPS (8).

RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC (RAR-related orphan receptor C) gene. RORγ is a member of the nuclear receptor family of transcription factors (9). Moreover, TH17 cells express the IL-23 receptor (IL-23R), and IL-23 is an important survival factor for TH17 cells and production of IL-17A. Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells.  In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates TH17 cells within dermis to make IL-17A and IL-22(10). In one study, expression of IL-17 mRNA (by in situ hybridization) and protein (by immunohistochemistry) in perivascular lymphocytes as well as in astrocyte and oligodendrocytes in CNS of MS patients was evident (7).

3 | Structure

Crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry shows a unique complex formation of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface (14). Unbound IL-17A homodimer is highly symmetric. Crystal structure analysis of homodimer IL-17A shows that two IL-17A monomers form a parallel dimer, and they are highly similar. Each IL-17A monomer contains a pair of anti-parallel β-sheets, one built from strands 1 and 2 and the second from strands 3 and 4 (Fig. 1a) (15). The overall structure adopts a cystine-knot fold (16). The structural analysis of IL-17A and IL-17A receptor shows that the D1 domain of IL-17RA interacts with both the  A and  B chains of IL-17A. IL-17RA D2 between the IL-17A/IL-17RA and IL-17F/IL-17RA complexes (Fig.2a). Binding to IL-17RA induces large conformational changes in the N-terminal region of the IL-17A dimer, but the C- terminal parts of both chains remain conformationally fixed. Because of these conformational changes, only 37 Cα atoms in chain A and 57 in chain B in the C-terminal half of the IL-17A dimer superimpose well with the unbound IL-17A dimer (rmsd 0.58 Å). Relative to the unbound IL-17A, the entire N-terminal half of chain A bends away from IL-17RA (Fig. 2b) (15).

Figure 1: Unbound IL-17A is highly symmetric

a) Wall-Eye stereo presentation of the overall structure of the unbound IL-17A dimer shown in ribbons (chain A, green; chain B, cyan), superimposed with its two-fold symmetry related dimer (gray). Least square superimposition was carried out using program LSQMAN (17). The N- and C termini and the secondary structural elements are labeled. Disulfide bonds are shown as yellow sticks. The same coloring scheme is used throughout this report, unless otherwise noted. Molecular pictures are prepared using program PyMol [18].

4 | Genetic Map:

IL-17A was originally discovered at transcriptional level by a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma, it was recognized to have homology to an open reading frame encoded within a T cell-tropic γ-herpesvirus, Herpesvirus Saimiri (22). IL-17A gene that encodes for IL-17A protein is present on chromosome 6, this gene has 1 transcript splice variant, 65 orthologues and 2 paralogues (23).

 

5 | Signaling Pathways of IL-17A and Subsequent Effects

CD4+ T helper cells can be modulated by their environment to produce different profiles of cytokines. A complex set of cytokines (namely, TGFβ, IL-6, IL-21 and IL-1, with some variations between mice and humans) can induce naive T cell differentiation into effector Th17 cells (24). TGF-β acting in the presence of proinflammatory cytokines, particularly IL-6, is sufficient to induce naive T cell differentiation into Th17 cells as shown in Figure 3 (25).

Figure 3 Th 17 cell differentiation in Mouse and Man [25]. (A) In mouse, naive T cells activated in the presence of TGF-β (possibly provided by Treg cells) and IL-6 begin differentiation toward the Th17 cell subset; IL-6 upregulates IL-21 and IL-23R to further their Th17 development. In the absence of IL-6, TGF-β instead induces regulatory T cells. Th17 cell development is inhibited by Th1 and Th2 cytokines, as well as IL-2 and retinoic acid. (B) In man, IL-23 or IL-1 drives differentiation of Th17 cells that express IL23R and CCR6. IL-1's effects may be enhanced by IL-23 and/or IL-6. Th1-cell-promoting cytokines inhibit Th17 cell development [25].

Figure 4 Th cell differentiation [26]. Antigen presenting cells release TGFβ Il21, IL-2, Il-23 and convert naïve T cells into Th17 effector cells which then release IL-17A that acts on the target cell and releases a variety of chemokines which then activate the host defense system with the recruitment of neutrophils [26]

Th17 cells produce additional cytokines besides IL-17A and IL-17F. IL-22, an IL-10 family cytokine, activates many of the same innate inflammatory genes as IL-17. Indeed, IL-17 and IL-22 act cooperatively on epithelial cells to induce inflammatory gene . As shown in Figure 4, activated Th17 cells release cytokines such as IL-17A, IL-17F and many others which act upon the target cell, as a result target cell releases chemokines/CAMs/G-CSF, acute phase proteins, antimicrobial proteins and inflammatory effector proteins which activate Host defense (recruitment of neutrophils) and autoimmunity inflammatory pathology (26).

Figure 5 IL-17A, IL-17F, IL-17A/F receptor, and ligand-receptor relationships and main structural features. FN, fibronectin III-like domain; SEFIR, SEF/IL-17R-related signaling domain; TILL, TIR-like loop; CBAD, C/EBPβ activation domain as shown [36].

After a brief description of the mechanism of action of IL-17A, a detailed mechanism of action is explained below. IL-17A and IL-17F, eponymous cytokines of the T_H17 cell lineage, are by far the best characterized. Both are covalent homodimers, and recent findings show that they also form IL-17A–IL-17F heterodimers (27,28). IL-17A–IL-17F heterodimers are produced at higher levels than IL-17A homodimers by human peripheral blood mononuclear cells in vitro (27).

IL-17A, IL-17F and IL-17A–IL-17F all signal through the same receptor subunits, IL-17RA and IL-17RC, which together form a heteromeric complex (29,30).

IL-17RA was initially identified as the receptor for mammalian IL-17A and vIL-17 (31). IL-17RA also binds IL-17F weakly, and is necessary for IL-17A, IL-17A/F and IL-17F mediated signal transduction (32). Affinity of IL-17RA for IL-17A is lower than the concentration required to mediate responses, which indicates that an additional subunit is involved in binding ligand and/or eliciting signaling (33).  Indeed, IL-17RA partners with IL-17RC to induce responses to IL-17A and IL-17F (34).

IL-17RA is expressed ubiquitously, with particularly high levels in hematopoietic tissue (35).Figure 6 IL-17A/IL-17RA, expression and known functions [26].

IL-17RA signaling, the NF-κB pathway:

IL-17A-induced genes showed that IL-17A activates a highly pro-inflammatory program of gene expression, typical of that induced by innate immune receptors such as IL-1R and TLRs (37). Similar to these receptors, IL-17A activates nuclear factor-κB (NF-κB), a transcription factor associated with inflammation (38). IL-17A activates p50 and p65, which are components of the classical NF-κB pathway (38). NF-κB-inducing kinase (NIK), which can mediate events in the non-classical pathway, was reported to be activated in response to IL-17A (39). IL-17A also induces the expression of IκBζ(37), which is a positive regulator of transcription by the TLR and IL-1R pathways(41).

Bioinformatics analysis that identified a conserved motif in the cytoplasmic domains of IL-17R-family members with homology to the Toll/IL-IR (TIR) domain. This study named the conserved IL-17R region a SEFIR domain, for SEF (similar expression to FGF receptor) /IL-17R. SEFIR domains lack certain elements found in prototypical TIR domains, potentially explaining why they do not engage TIR-containing adaptors. Specifically, SEFIR domains lack the TIR Box 3 subdomain and the BB-loop (42), which are crucial specificity determinants directing TIR-based protein–protein interactions. A region C-terminal to the SEFIR domain in IL-17RA has marked sequence homology to BB-loops. Deletion of or point mutations in this region render IL-17RA non-functional, and so this motif is referred to as a “TIR-like loop” (TILL) (44). The TILL domain is unique to IL-17RA (42). A SEFIR domain is also present in ACT1, a signaling adaptor that was previously linked to NF-κB activation through BAFF (B cell activating factor) and CD40L (42).

IL-17RA signalling, AP1, MAPK and mRNA stability:

Proinflammatory mediators activate the mitogen-activated protein kinase (MAPK) pathway, which leads to the activation of AP1 transcription factors. IL-17A activates various MAPKs, but ERK is generally the most strongly and rapidly phosphorylated. Although AP1 binding sites are enriched in IL-17A target promoters (44), the AP1 site in the mouse Il6 promoter is dispensable for IL-17A-mediated activation (38). MAPK pathway regulates the pathway of IL-17A induced genes through control of mRNA transcript stability. MAPK stabilizes mRNA through the inhibition of destabilizing proteins such as tristetraprolin (TTP). TTP binds to AU-rich elements (AREs) in mRNA transcripts and delivers them to the exosome complex, where they are degraded. Phosphorylation of TTP by MAPK blocks its ability to recruit the degradative machinery, thus increasing mRNA transcript half-life. Many IL-17A target genes are chemokines or cytokines whose transcripts are stabilized by AREs located in the 3′ UTR (45). Activation of MAPK by IL-17A increases the concentration of these transcripts significantly (46). ACT1 is required for IL-17A-mediated stabilization of CXCL1 (also known as Groα or KC) mRNA, but TRAF6 is not required (47). In addition to TTP, other proteins are involved in mediating cytokine mRNA stability such as the recently described Zc3hl2a gene (48).

IL-17RA signaling, C/EBP:

IL-17A is a weak activator of NF-κB, suggesting the involvement of additional transcription factors in the response to IL-17. A microarray screen for IL-17A-induced genes identified the CCAAT/enhancer binding protein transcription factors C/EBPβ and C/EBPδ(38). The promoters of genes upregulated by IL-17A are enriched for C/EBP binding elements (44), and activation of the Il6 and lcn2 (lipocalin 2, also known as 24p3) promoters have an absolute requirement for C/EBPβ/γ following IL-17A stimulation (38). So, C/EBPβ and C/EBPδ are targets of IL-17A signaling and also important mediators of IL-17A-induced signaling pathways. ACT1 and the SEFIR and TILL domains of IL-17RA are required for the induction of C/EBPδ . This observation is consistent with a study showing that NF-κB can bind directly to the C/EBPδ promoter after LPS stimulation (49).

C/EBPβ expression is regulated by IL-17A in a more complex manner. C/EBPβ exists in three isoforms that are generated by alternative translation (50). The largest is a full-length isoform known as liver enriched activator protein (LAP). A shorter form, LAP, is generated from an alternative start codon and is thought to be the most transcriptionally active form of C/EBPβ. LIP (liver-enriched inhibitory protein) is also generated by alternative translation, and acts as a dominant negative inhibitor. IL-17A treatment of fibroblast cell lines result in a mild induction of LAP, a large increase in LAP and no induction of LIP. Induction of LAP depends on the SEFIR/TILL domain of IL-17RA, suggesting that this process is downstream of ACT1. Generation of LAP also requires a poorly-characterized C-terminal domain in IL-17RA known as a C/EBPβ-activation domain (C-BAD) (43).

Post-translational modifications of C/EBPβ such as phosphorylation are important for its activity (50). IL-17A triggers dual, sequential phosphorylation of a regulatory site within C/EBPβ. ERK phosphorylates one site (Thr-188) within 15 minutes of IL-17A stimulation. However, GSK (glycogen synthase kinase)-3β phosphorylates Thr-179 only after 1 hour, an event that requires prior phosphorylation at Thr-188 (51). Interestingly, these phosphorylation events are mediated by distinct subdomains of IL-17RA. Regulation of ERK and hence phosphorylation at Thr-188 is mediated by the SEFIR–TILL region (43). By contrast, regulation of GSK3β is mediated by the C-BAD motif. In other systems PI3K signaling is upstream of GSK3β, but standard PI3K inhibitors have no effect on IL-17A signaling in this setting. Unexpectedly, the consequence of C/EBPβ phosphorylation is to downregulate its transcriptional capacity, and so this pathway is one of the few known inhibitory signaling events mediated by IL-17A (51).

6 | Immune Mediated Inflammatory    Diseases

Interleukin-17A play roles in human disease pathogenesis based on the presence of IL-17A in the skin and/or joints of patients with immune-mediated diseases such as psoriasis, rheumatoid arthritis (RA) and psoriatic arthritis (PsA) (52,53).

Psoriatic arthritis (PsA) is the second most common inflammatory arthropathy, after rheumatoid arthritis and most patients have established psoriasis, often for years, prior to the onset of joint pain and swelling; in addition, associated features of nail disease, dactylitis, enthesitis, spondylitis or uveitis may be present. Psoriasis may not be immediately apparent, as small or patchy lesions may occur in the scalp or perineum. PsA presents as a symmetrical polyarthritis, similar to rheumatoid arthritis, or an asymmetrical oligoarthritis with a predilection for the distal interphalangeal joints. Moreover, Spinal involvement is similar, although not identical, to ankylosing spondylitis and joint damage occurs early; up to 50% of PsA patients have an 11% annual erosion rate in the first 2 years of disease duration, suggesting that it is not a benign condition (70).

Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumor-like behavior of rheumatoid synovium, and autoantibodies have also been implicated (71).

IL-17A in psoriatic arthritis:

Psoriatic arthritis impacts an estimated 20–30% of psoriasis patients and its onset is, on average, a decade later than cutaneous disease (54). IL-17A-producing cells, including Th17 cells and c-Kit-positive mast cells, are increased in the synovial fluid of patients with PsA(55,56). Synovial fibroblasts isolated from PsA patients exhibited higher IL-17RA expression compared with cells from patients with osteoarthritis, and they produced higher levels of IL-6, CXCL-8 and matrix metalloproteinase 3 in response to IL-17A (55). Additionally, research indicates that mutant Act1, in some cases of PsA, can differentially decrease TRAF6 versus TRAF2/5 signaling (56, 57).

IL-17A in rheumatoid arthritis:

In rheumatoid synovial explants functional amounts of IL-17A exhibited IL-17A-positive cells in T-cell-rich synovial regions (58). High levels of IL-17A in the rheumatoid synovium, sub lining layer and at the margins of lymphocytic aggregates have been found (59).

Elevated levels of IL-17A were detected in serum and synovial fluid of patients with RA (60,61). Moreover, they were associated with greater disease activity as reflected by the DAS28 and the presence of anti-citrullinated peptide antibodies (60,62). Interleukin-17A mRNA expression in synovial membranes is strongly correlated with markers of inflammation such as elevated peripheral blood C-reactive protein (CRP), which is predictive of joint damage progression and showed interaction with TNF expression, particularly in disease of shorter duration (62).

Interleukin-17A enhances the production of chemokines such as CCL2, CCL20, CXCL-8 and cytokines such as TNF, IL-1β, IL-6 from synovial fibroblasts (64), additionally, it increases the production of cartilage-degrading matrix metalloproteinases, and blocks new matrix synthesis by chondrocytes (65,66). Moreover, it stimulates bone resorption by enhancing receptor activator of NF-κB (RANK) ligand expression on osteoblasts and RANK on osteoclast precursors, as well as via increased cytokine production (67,68). Both IL-17A and TNF up-regulate the production of vascular endothelial growth factor in cultured rheumatoid synovial fibroblasts, which may be important in pannus formation (69).

7 | Autoimmune Disease

Multiple sclerosis (MS) is a disease that affects the central nervous system (CNS), including the brain, spinal cord and optic nerves (72). MS is characterized by overall reduction in CNS volume, and by accumulation of immune cells mainly in the white matter of various CNS areas, although substantial number of plaques can be found in the grey matter, leading to formation of localized inflammatory foci (73). Inflammatory processes in these foci cause damage to myelin and destruction of oligodendrocytes (73).

Studies have shown that myelin-specific CD4⁺ T cells that have developed in peripheral lymphoid organs infiltrate the CNS, where they encounter their associated antigens presented by local antigen presenting cells (APC). This interaction with APCs leads to re-activation of myelin-specific CD4⁺ T cells, which in turn activate APCs by cell-cell contact and by secreted pro-inflammatory products, such as cytokines and chemokines. Secretion of pro-inflammatory mediators attracts various immune cells into the CNS, where they are activated and start secreting mediators that damage surrounding CNS tissue, leading to formation of lesions and eventually to neurologic deficits

IL-17A in MS:

Immunization with myelin antigen induces

development of Th17 cells in the presence of IL-13. These myelin-specific Th17 cells traffic into the CNS, where they secrete IL-17A, which through chemokine induction attracts various immune cells, and in particular myeloid cells, into the CNS, initiating and maintaining the inflammatory cascade. However, subsequent studies have shown that IL-17A plays a contributing, but non-essential, role in EAE, as in most studies lack of IL-17A bioactivity led to mitigated disease course and improved recovery, but did not confer resistance to disease (74,75).

8 | Drug to inhibit IL-17A

Secukinumab (Cosentyx) is a fully human anti-IL-17A IgG1κ monoclonal antibody (77). In 2015, it was approved in the US and in Europe as a first line drug for the treatment of moderate-to-severe plaque psoriasis (78). Cosentyx is administered 

Figure 8: Th1/Th17 paradigm of CNS inflammatory demyelination. In the peripheral immune system, IL-12 and IL-23, produced by dendritic cells, induces the differentiation of Th1 and Th17 cells, respectively. IL-12 is not strictly required and may actually play an immunoregulatory role in development of EAE, as mice that do not produce, or cannot respond to, IL-12 develop severe EAE. Activated Th1 and Th17 cells migrate into the CNS across the blood-brain barrier. In the CNS, myelin-reactive Th cells interact with resident microglia and are reactivated upon recognition of myelin antigens. Activated effector Th cells produce cytokines and chemokines that lead to an inflammatory pathological cascade in the CNS and damage to the myelin sheath and neuronal axons. (Figure first published in Drug News & Perspectives 19(2):77-83, 2006, Touil T et al., Pathophysiology of Interleukin-23 in experimental autoimmune encephalomyelitis [76]

subcutaneously with a 300 mg dose at weeks 0, 1, 2, 3, 4, and every 4 weeks thereafter (78). A 150 mg dose is also approved for use (77).

9 | Side Effects of inhibiting IL-17A

The role of Th17 cells and their effectors in host defense suggests that IL-17A inhibition could increase the risk of serious infection and various immune-mediated disorders. Patients with genetic defects in IL-17RA or IL-17F exhibit chronic mucocutaneous candidiasis, characterized by recurrent or persistent skin, nail and mucosal infections caused by Candida albicans, and to a lesser extent by Staphylococcus aureus (79).  Cellular responses to IL-17A and IL-17F were removed in those with IL-17RA deficiency, whereas IL-17F deficiency resulted in impaired cellular responses. Autoimmune polyendocrine syndrome type 1, caused by mutations in the autoimmune regulator (AIRE) gene that normally controls thymic self-tolerance, is associated with autosomal recessive chronic mucocutaneous candidiasis (80,81). In these patients, the candidiasis appears associated with the presence of autoantibodies against Th17 cytokines including IL-17A, IL-17F and/or IL-22. Patients with autosomal dominant mucocutaneous candidiasis have mutations in the coiled-coil domain of the signal transducer and activator of transcription 1 (STAT1) gene, which impairs IL-12 or IL-23 signaling, resulting in defective Th1 and Th17 responses, respectively (82). Patients with hyper-IgE syndrome caused by an autosomal dominant STAT3 deficiency have a low proportion of IL-17A-producing circulating T cells and exhibit mucocutaneous infections typically caused by S. aureus and C. albicans (83). These findings show that inhibition of IL-17A could lead to mucocutaneous infections.

IL-17A is involved in controlling fungal infection. In one study, a blockade of IL-17A by neutralizing antibodies during Pneumocystis carinii infection significantly increased the pathogen burden and exacerbated the disease (84). Suppression of IL-17A could lead to severe side effects in irritable bowel syndrome rather being therapeutic. After activation, naïve CD4-T cells differentiate into three subsets of Th effector cells, each subset having a unique cytotoxic profile and specific biological functions. Treg cells that differentiate in the presence of the Foxp3 transcription factor (90-100 amino acids that form a DNA binding motif) produce anti-inflammatory mediators such as IL-10 and TGF-β, whose function is to preserve immune tolerance and homeostasis (86).

Th17 cells also possess a regulatory function recently described as human IL-17-producing Foxp3⁺/RORγt double positive T-cells (87). In conclusion, the effector lymphocytes are not terminally differentiated. They may differentiate into regulatory pathways and alternative effectors under the local immunological pressure (88).

In patients with Irritable bowel disease the prevalence of circulating Foxp3 DE CD4 (+) and IL-17 T cells is increased and the coexpression of Foxp3 and RORγt in these cells requires conversion from Treg cells to Th17 cells associated with a decreased suppressive function of Foxp3 CD4(+) T lymphocytes (89).

To eliminate these side effects future studies should focus on the role of the inhibition of IL-17A and IL-17F together, as it is known from previous studies that IL-17A and IL-17F both are produced by Th 17 cells along with other cytokines in response to APC (34). It would be interesting to see the impact of inhibition of both IL-17A and IL-17F in regulating these side effects. In most of the therapies only IL-17A is inhibited; there might be a cooperation between IL-17A and IL-17F, or inhibition of IL-17A may have some unknown impact of IL-17A which is leading to the above-mentioned side effects.

However, most effective therapy could be treating patients’ individually. Individualized treatment will allow for specific target with individualized dosage of the drug. Treating everyone with same dosage could be another issue that leads to side effects in patients. It might be possible that not every patient requires the equal suppression of IL-17A or IL-17F which is causing the side effects, as suppression in one patient may be more than or less than the required amount in another patient.

Additionally, we should not forget there is not only CD4+ Th 17 cells that produce IL-17A.CD8+ T cells, Neutrophils such as γδ T and unconventional αβ T cells are also responsible for producing IL-17A. Future studies should be looking at each one of these cells as potential targets. As it might be possible that suppression of one type of cell activity might not impact the activity of another, and there could be possibly a middle way that could lead to balance of IL-17A in immunoinflammatory, autoimmune, and Irritable bowel disease.

Moreover, possible therapeutic targets could be IL-RA and IL-RC receptors; suppressing one of the receptors and not the other could lead to a balanced amount of IL-17A in the body which would not manifest any side effects.

The key is in specifying the targets which could be Act1 adopter protein, or any of the transcription factors involved in disease pathology. Also, making individualized therapies for each patient could lead to a better outcome.

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