Gut-Busters: IL-17 Ain't Afraid of No IL-23.

Interleukin-23 (IL-23) is considered a critical regulator of IL-17 in lymphocytes. Whereas antibodies targeting IL-23 ameliorate colitis, IL-17 neutralization exacerbates disease. In this issue, Cua and colleagues and Maxwell and colleagues show that IL-17 maintains intestinal barrier integrity, helping explain this dichotomy (Lee et al., 2015; Maxwell et al., 2015).

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.

Critical role of IL-25-ILC2-IL-5 axis in the production of anti-Francisella LPS IgM by B1 B cells.

B1 cells, a subset of B lymphocytes whose developmental origin, phenotype, and function differ from that of conventional B2 cells, are the main source of "natural" IgM but can also respond to infection by rapidly producing pathogen-specific IgM directed against T-independent antigens. Francisella tularensis (Ft) is a Gram-negative bacterium that causes tularemia. Infection with Ft Live Vaccine Strain activates B1 cells for production of IgM directed against the bacterial LPS in a process incompletely understood. Here we show that immunization with purified Ft LPS elicits production of LPS-specific IgM and IgG3 by B1 cells independently of TLR2 or MyD88. Immunization, but not infection, generated peritoneum-resident memory B1 cells that differentiated into LPS-specific antibody secreting cells (ASC) upon secondary challenge. IL-5 was rapidly induced by immunization with Ft LPS and was required for production of LPS-specific IgM. Antibody-mediated depletion of ILC2 indicated that these cells were the source of IL-5 and were required for IgM production. IL-25, an alarmin that strongly activates ILC2, was rapidly secreted in response to immunization or infection and its administration to mice significantly increased IgM production and B1 cell differentiation to ASC. Conversely, mice lacking IL-17RB, the IL-25 receptor, showed impaired IL-5 induction, IgM production, and B1 ASC differentiation in response to immunization. Administration of IL-5 to Il17rb-/- mice rescued these B1 cells-mediated responses. Il17rb-/- mice were more susceptible to infection with Ft LVS and failed to develop immunity upon secondary challenge suggesting that LPS-specific IgM is one of the protective adaptive immune mechanisms against tularemia. Our results indicated that immunization with Ft LPS triggers production of IL-25 that, through stimulation of IL-5 release by ILC2, promotes B1 cells activation and differentiation into IgM secreting cells. By revealing the existence of an IL-25-ILC2-IL-5 axis our results suggest novel strategies to improve vaccination against T-independent bacterial antigens.

IL-17 Receptor C Signaling Controls CD4+ TH17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases.

BACKGROUND: IL-17A-producing CD4+ T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4+ T cell subsets, remains to be elucidated. METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4+CD45RBhigh T cell transfer colitis model. RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4+ T cells and, most importantly, specifically in CD4+ TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4+ TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.

From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment.

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural-containing a SEFIR/TILL domain-and functional-requiring ACT-1 for signaling-properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.

Functional specialization of interleukin-17 family members.

Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.

Cytokines of the IL-17 family in psoriasis.

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-to-date overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation.

The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced TH17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH17 cells, and loss of this expression prevented the TH17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH17-induced autoimmune disorders.

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium.

A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multistep process that involves sequential cell-cell interactions of circulating leukocytes with IL-1- or TNF-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a proinflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, although neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA sequencing analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and they also stimulate neutrophil production of proinflammatory molecules, including TNF, IL-1α, IL-1ß, and IL-8. Furthermore, IL-17-activated PCs, but not ECs, can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondrial outer membrane permeabilization and caspase-9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by conditioned media from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.

Altered expression of microRNAs in patients with pouchitis after restorative proctocolectomy.

BACKGROUND AND PURPOSE: Pouchitis is the most common long-term complication of restorative proctocolectomy with ileal pouch-anal anastomosis. We investigated alterations in the expression of microRNAs, noncoding RNAs that act as potent negative regulators of gene expression, in pouchitis. METHODS: The subjects of this study were 16 patients with diagnosed pouchitis and 48 patients without pouchitis after restorative proctocolectomy, performed for ulcerative colitis. Total RNA was extracted from biopsies and microRNAs were quantified using a real-time polymerase chain reaction. RESULTS: The expression of microRNA 21 and 223 was higher, whereas that of microRNA 192 and 196a was lower, in the inflamed mucosa from the pouchitis patients than in the mucosa from the non-pouchitis patients. The levels of 14 microRNAs were significantly lower in the mucosa from the pouchitis patients, than in the non-inflamed proximal ileal mucosal samples. The expression of microRNA 192 was remarkably reduced in pouchitis. A significant negative correlation was found between microRNA 192 and interleukin 17 receptor A mRNA levels. CONCLUSIONS: Significant alteration in miRNA expression in line with inflammatory bowel disease was evident in the mucosa from the pouchitis patients. Interleukin 17 receptor A may be involved in the pathogenesis of pouchitis through the downregulation of microRNA 192.

IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma.

Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL-25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL-17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity.

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.

UNLABELLED: Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA(-/-) mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA(-/-) mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. CONCLUSION: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition.

IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction.

IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and ß isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1ß and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation.

Therapeutic Potential of IL-17-Mediated Signaling Pathway in Autoimmune Liver Diseases.

Emerging evidence reveals that various cytokines and tissue microenvironments contribute to liver inflammation and autoimmunity, and IL-17 family is one of highlights acknowledged. Although the implication of IL-17 family in most common autoimmune diseases (such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis) has been extensively characterized, the role of this critical family in pathophysiology of autoimmune liver diseases (AILD) still needs to be clarified. In the review, we look into the intriguing biology of IL-17 family and further dissect on the intricate role of IL-17-mediated pathway in AILD. Considering encouraging data from preclinical and clinical trials, IL-17 targeted therapy has shown promises in several certain autoimmune conditions. However, blocking IL-17-mediated pathway is just beginning, and more fully investigation and reflection are required. Taking together, targeting IL-17-mediated responses may open up new areas of potential clinical treatment for AILD.

Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis.

Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases.

Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

BACKGROUND: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. METHODS: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. RESULTS: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. CONCLUSIONS: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

Participation of interleukin 17A in neuroimmune interactions.

Inflammation involving the helper T cell 17 (Th17) subset of lymphocytes has been implicated in a number of diseases that affect the nervous system. As the canonical cytokine of Th17 cells, interleukin 17A (IL-17A) is thought to contribute to these neuroimmune interactions. The main receptor for IL-17A is expressed in many neural tissues. IL-17A has direct effects on neurons but can also impact neural function via signaling to satellite cells and immune cells. In the central nervous system, IL-17A has been associated with neuropathology in multiple sclerosis, epilepsy syndromes and ischemic brain injury. Effects of IL-17A at the level of dorsal root ganglia and the spinal cord may contribute to enhanced nociception during neuropathic and inflammatory pain. Finally, IL-17A plays a role in sympathetic axon growth and regeneration of damaged axons that innervate the cornea. Given the widespread effects of IL-17A on neural tissues, it will be important to determine whether selectively mitigating the damaging effects of this cytokine while augmenting its beneficial effects is a possible strategy to treat inflammatory damage to the nervous system.

The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment.

RATIONALE: Atherosclerosis is a disease of large- and medium-sized arteries that is characterized by chronic vascular inflammation. While the role of Th1, Th2, and T-regulatory subsets in atherogenesis is established, the involvement of IL-17A-producing cells remains unclear. OBJECTIVE: To investigate the role of the IL-17A/IL-17RA axis in atherosclerosis. METHODS AND RESULTS: We bred apolipoprotein-E-deficient (Apoe(-/-)) mice with IL-17A-deficient and IL-17 receptor A-deficient mice to generate Il17a(-/-)Apoe(-/-) and Il17ra(-/-)Apoe(-/-) mice. Western diet fed Il17a(-/-)Apoe(-/-) and Il17ra(-/-)Apoe(-/-) mice had smaller atherosclerotic plaques in the aortic arch and aortic roots, but showed little difference in plaque burden in the thoracoabdominal aorta in comparison with Apoe(-/-) controls. Flow cytometric analysis of Il17a(-/-)Apoe(-/-) and Il17ra(-/-)Apoe(-/-) aortas revealed that deficiency of IL-17A/IL-17RA preferentially reduced aortic arch, but not thoracoabdominal aortic T cell, neutrophil, and macrophage content in comparison with Apoe(-/-) aortic segments. In contrast to ubiquitous IL-17RA expression throughout the aorta, IL-17A was preferentially expressed within the aortic arch of WD-fed Apoe(-/-) mice. Deficiency of IL-17A or IL-17RA reduced aortic arch, but not thoracoabdominal aortic TNFα and CXCL2 expression. Aortic vascular IL-17RA supports monocyte adherence to explanted aortas in ex vivo adhesion assays. Short-term homing experiments revealed that the recruitment of adoptively transferred monocytes and neutrophils to the aortas of Il17ra(-/-)Apoe(-/-) mice is impaired in comparison with Apoe(-/-) recipients. CONCLUSIONS: The IL-17A/IL-17RA axis increases aortic arch inflammation during atherogenesis through the induction of aortic chemokines, and the acceleration of neutrophil and monocyte recruitment to this site.

Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma.

RATIONALE: IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment. OBJECTIVES: To determine efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids. METHODS: Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation. MEASUREMENTS AND MAIN RESULTS: Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction. CONCLUSIONS: Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).

TH17 cells in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset T(H)17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for T(H)17 cells in severe, steroid-insensitive asthma and COPD.