Inborn errors of IL-6 family cytokine responses.

The IL-6 family of cytokines mediates functions in host protective immunity, development of multiple organs, tissue regeneration and metabolism. Inborn errors in cytokines or cytokine receptor units highlight specific roles for IL-6, IL-11, LIF, OSM, and CLC signaling whereas incomplete loss-of-function variants in the common receptor chain GP130 encoded by IL6ST or the transcription factor STAT3, as well as genes that affect either GP130 glycosylation (PGM3) or STAT3 transcriptional control (ZNF341) lead to complex phenotypes including features of hyper-IgE syndrome. Gain-of-function variants in the GP130-STAT3 signaling pathway cause immune dysregulation disorders. Insights into IL-6 family cytokine signaling inform on therapeutic application in immune-mediated disorders and potential side effects such as infection susceptibility.

Current Opinion in Immunology 2021, 72:135–145

This review comes from a themed issue on Host pathogen

Edited by Helen C Su and Jean-Laurent Casanova

For a complete overview see the and the

Available online 24th May 2021

0952-7915/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Cellular communication via cytokines is a key aspect of host protective immunity [1]. The interleukin (IL-) 6 family cytokines consist of at least ten cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory factor (LIF), IL-35, IL-39, cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), and ciliary neurotrophic factor (CNTF) [2]. The IL-6 family cytokines and their specific receptors have a conserved common signal transducing protein, GP130 encoded by IL6ST forming multimeric complexes. IL-6 and IL-11 bind to their respective receptors IL-6Rα and IL-11Rα before interacting with two GP130 molecules to form a hexamer in a 2:2:2 configuration. By contrast, LIF and OSM form heterotrimeric complexes with their receptor chains and GP130 with a valence of 1:1:1 [2,3]. The heterodimeric cytokine IL-27 associates with its heterodimeric cytokine receptor complex, IL-27R (WSX-1)-GP130 [4]. Formation of these receptor complexes recruits members of the Janus kinase family of tyrosine kinases (JAK1, JAK2 and TYK2), which then phosphorylate the tyrosine sites within the intracellular domain of GP130 [2]. This results in activation of signaling cascades including the tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), STAT1 and mitogen activated protein kinase pathways. The combinatorial array of cell type-specific and context-specific expression of cytokines and receptor complexes is responsible for a diverse range of functions in host protective immunity, organ development, and metabolism.

A number of distinct Mendelian disorders are caused by inborn errors in individual components of the IL-6 family of cytokines and their downstream signaling pathways. Defects in genes that encode cytokines (OSM, CLCF1) or cytokine receptors (IL6R, IL11R, OSMR, LIFR) illustrate the function of individual cytokines in immune and non-immune cell communication, whereas defects in shared components of the signaling machinery, in particular STAT3 and the common cytokine receptor chain GP130, present with overlapping phenotypes such as hyper-IgE syndrome (HIES). In addition to genetic defects that directly affect the IL-6 cytokine family signalling machinery, there are genetic defects that affect IL-6 cytokine family responses indirectly via effects on the transcriptional control of signalling components (such as STAT3), or post-translational modification (such as glycosylation of GP130) or interference with cross-regulatory non-canonical pathways (such as the STAT3-ERBIN-TGF-β signalling). An integrated analysis allows dissection of the contribution of individual cytokines towards overlapping phenotypes and informs treatment options for patients with Mendelian disorders and immune-mediated disorders (Figure 1).

Figure 1

Structural features of the IL-6 family cytokine complexes and associated human phenotypes.

Upon cytokine ligand engagement, GP130 forms hexameric (IL-6 and IL-11) and heterotrimeric (or heteroquaternery) complexes (IL-27, OSM, LIF, CT-1, CLC and CNTF) with subsequent signal transduction mediated through the JAK/STAT pathway and canonical STAT3 activation. The IL-6 family related cytokine IL-31 is shown since it signals via overlapping receptors and explains combinatorial phenotypes. Mendelian disorders caused by defects in IL-6 family cytokine signalling components are illustrated and inheritance patterns are indicated.

Human disorders associated with defects in IL-6 family cytokines

IL-6 receptor defects cause immunodeficiency and atopy

IL-6 has a broad effect on hematopoietic and non-hematopoietic cells. In CD4+ T helper (Th) cells, IL-6 drives differentiation of activated naïve Th cells into IL-17 and IL-22 expressing Th17 and Th22 cells, key for anti-bacterial and anti-fungal defense. Conversely, IL-6 inhibits differentiation of CD4+ T regulatory cells, which play a key role in restraining inflammatory responses. In hepatocytes, IL-6 induces inflammation-induced acute phase proteins including C-reactive protein (CRP) [2]. Patients with loss-of-function variants in IL-6R present with autosomal recessive (AR) disorder characterized by recurrent Haemophilus chest infections, staphylococcal skin abscesses, atopic dermatitis, elevated IgE levels, eosinophilia and absent acute phase responses [5,6]. Despite elevated serum IL-6 levels, CRP was undetectable during infection in those patients. Detectable numbers of Th17 cells are seen in these patients.

IL-11 receptor defects cause craniosynostosis and dental anomalies

IL-11 is crucial for bone and tooth development. Biallelic loss-of-function variants in IL-11RA lead to craniosynostosis, maxillary hypoplasia, dental and minor digit abnormalities with an AR mode of inheritance [7]. Those patients do not present with increased susceptibility to infections.

LIF receptor defects cause Stüve-Wiedemann syndrome

LIF regulates embryonic organogenesis, bone remodeling, neural regeneration, and reproduction [2,8]. Human LIFR deficiency caused by biallelic loss-of-function LIFR variants is associated with AR Stüve-Wiedemann syndrome, a pre-natally to peri-natally fatal condition characterized by severe skeletal dysplasia, pulmonary dysfunction, and dysautonomia [9] as well as urinary tract malformation [10].

CLC deficiency and cold-induced sweating syndrome

The neurotrophic cytokines CT-1, CLC and CNTF are key for survival of motoneurons in mice [2]. The only human deficiency in a neurotrophic cytokine is CLC deficiency, caused by biallelic mutations in the CLCF1 gene, that manifests as AR cold-induced sweating syndrome along with congenital abnormalities including mild facial weakness, high arched palate, and thoracolumbar scoliosis [11].

OSM deficiency and OSM receptor signalling defects affect hematopoiesis and cause skin disease

OSM plays important roles in hematopoiesis, liver repair, cardiac tissue remodeling and maintenance of intestinal inflammation [2]. Patients with inherited defects in OSM present with anemia and thrombocytopenia [Lagresle-peyrou et al., abstract ESID7-0268, The European Society For Immunodeficiencies, Edinburgh, Sepember 2017]. Monoallelic loss-of-function OSMR mutations underlie autosomal dominant (AD) familial primary localized cutaneous amyloidosis. OSMR forms heterodimers with either GP130 and IL-31RA and inherited defects in OSMR are associated with reduced but not absent OSM and defective IL-31 signaling [12]. Therefore, the defect in the OSMR highlights the role of IL-31, a cytokine that is related to the IL-6 family, signaling via the OSMR and the IL-31R but does not require GP130 [13].

The cytokines IL-27, IL-35 and IL-39

So far, no human Mendelian disorders have been reported that selectively affect the cytokines IL-27, IL-35, and IL-39. IL-27 drives differentiation of interferon-γ-expressing Th1 cells that are key for clearing intracellular infections including viruses, tuberculosis and toxoplasma in model systems. Conversely, it enhances their expression of IL-10 and the anti-inflammatory co-receptor ligand programmed death-ligand 1 [4]. IL-27R deficient mice infected with toxoplasma die from over exuberant cerebral inflammation rather than a failure to clear the parasite [14]. IL-35 and IL-39 share the EBI3 subunit with IL-27. IL-35 has been reported to drive regulatory functions in B and Th cells [15,16]. In contrast, IL-39 deficiency in B cells induces lupus-like inflammation in mice [17].

Hyper-IgE syndrome is associated with impaired STAT3 signaling

Hyper-IgE syndrome is a primary immunodeficiency characterized by elevated IgE levels, eosinophilia, impaired acute phase response during infections and susceptibility to staphylococcal and fungal lung and skin infections, including chronic mucocutaneous candidiasis [18, 19, 20]. Resolution of pneumonias is associated with breakdown of lung tissue leading to pneumatoceles and bronchiectasis that can be the site of secondary infections. Many aspects of viral immunity are preserved although there is a loss of T cell memory that leads to an increased incidence of recurrence of latent viral infections such as varicella zoster and Epstein–Barr viral infections [21]. In addition to defects in immunity, patients may present with skeletal disorders including deciduous tooth retention, scoliosis and vascular aneurysms [20]. In this review, we summarize and compare the clinical features and infection susceptibility in patients with IL-6 signaling defects that resemble HIES (Table 1, Table 2).

Table 1

Comparative analysis of clinical features presenting in patients with IL-6 signaling defects (modified after Refs. [5,29,30])

	STAT3	IL6R (n = 6) [5••,6••]	GP130	GP130	GP130	ZNF341	PGM3
	HIES (n = 145) [70,71]		AR defect (n = 3) [29•,30,31••]	AD defect (n = 12) [32••]	Complete	Deficiency (n = 19) [36,37]	Deficiency (n = 26) [38, 39, 40]
					Loss-of-function (n = 5) [28••]
Gene defect	STAT3	IL6R	IL6ST	IL6ST	IL6ST	ZNF341	PGM3
HIES class	HIES1	HIES5	HIES4	–	–	HIES3	–
Inheritance	AD	AR	AR	AD	AR	AR	AR
IgE	↑↑	↑↑	↑	↑	N/K	↑↑	↑↑
Eosinophilia	++	+	++	++	–	+	++
Dermatitis	++	++	+	++	+	++	++
Food allergies	++	–	+	+	–	+	++
Asthma	+	+	–	++	N/K	–	++
Infections
Bacterial skin abscesses	++	++	+/−	++	N/K	++	++
Bacterial pneumonia	++	++	++	++	N/K	++	++
Fungal infections	++	–	–	++	N/K	++	++
Viral infections	+	–	–	–	N/K	–	++
Parenchymal lung abnormalities
Bronchiectasis	++	–	+	++	N/K	++	++
Pneumatocele	++	–	–	++	N/K	++	–
Dysmorphia
Prominent forehead/characteristic face	++	–	+	++	–	+	+
Decidual teeth retention	++	–	++	++	–	+	–
craniosynostosis	+	–	++	–	–	–	–
Psychomotor retardation	+/−	–	+	–	+	–	++
Neoplasia	+	–	–	–	N/K	–	+
Immunological features
Immunoglobulin A/G/M	Normal	Normal/low	Normal	Normal	N/K	Normal/↑IgG	Normal
Lymphopenia	–	–	–	–	N/K	+/−	+
CD4 lymphopenia	–	–	–	–	N/K	+/−	+
Th17 cells	Low	Normal/low	Normal/low	Normal	N/K	Low	Normal
CD19+ B cells	Normal/low	Normal	Normal/low	Normal	N/K	Normal	Normal/low
Switched memory B cells	Low	Low	Normal/low	Low	N/K	Low	Normal/low

i) There is genetic heterogeneity of HIES, with five classes of genotypes been identified (HIES1-5).

ii) Apart from STAT3, the phenotypical comparisons are made based on limited number of published cases. More data are needed to describe the phenotype extensively.

iii) ++ and + indicate greater and less than 10% of patients with the feature from the cohorts respectively whereas – indicates the feature not reported.

iv) ↑↑ refers to IgE levels >5000 IU/mL; ↑ refers to IgE levels 2000–5000 IU/mL. N/K: unknown.

Table 2

Infection susceptibility by microbes in patients with IL-6 signaling defects

	STAT3	IL6R (n = 6) [5••,6••]	GP130	GP130	GP130	ZNF341	PGM3
	HIES (n = 145) [70,71]		AR defect (n = 3) [29•,30,31••]	AD defect (n = 12) [32••]	Complete	Deficiency (n = 19) [36,37]	Deficiency (n = 26) [38, 39, 40]
					Loss-of-function (n = 5) [28••]
Gene defect	STAT3	IL6R	IL6ST	IL6ST	IL6ST	ZNF341	PGM3
Infections by microbes
Bacterial	Staphylococcus aureusa,b,h,i,g, Pseudomonas aeruginosaa,h, Streptococcus pneumoniaea,h,i, Stenotrophomonas maltophiliaa, Haemophilus influenzaea,h, Mycobacterium pneumoniaea, Mycoplasma pneumoniaea, Enterobacteriaa, Anaerobic bacteriaa, Branhamella catarrhalisa, Klebsiella sppa, Prevotella oralisa, Moraxella catarrhalis,a,h, Escherichia colie,h	Staphylococcus aureusb, Haemophilus influenzaea,b, Moraxella catarrhalisa, Escherichia colia	Staphylococcus aureusa,f,j, Streptococcus group Ab,f,i or milleria or agalactiaej, Serratia marcescensa, Pseudomonas aeruginosaa	Staphylococcus aureusa,b, Haemophilus influenzaea, Escherichia colie, Pseudomonas aeruginosac	lack of infectionsk	Staphylococcus aureusb, Streptococcus dysgalactiaeb	Staphylococcus aureusb, Pseudomonas aeruginosab, Streptococcus pneumoniaeg, Klebsiella pneumoniaeb, Enterococcus cloacaeb, Streptococcus dysgalactiae equisimilisb, Streptococcus group Ab
Fungal	Candida albicansb, Candida glabratab, Candida parapsilosisb, Aspergillus fumigatusa, versicolor or spp.a, Cryptococcus laurentiib, Pneumocystis jiroveciia, Trichophyton rubrumb, Trichophyton mentagrophytesb			Aspergillus fumigatua,b, Alternariab	lack of infectionsk	Candida albicansc, Candida glabratac, Candida parapsilosisd, Aspergillusb	Candidab,c,d
Viral	Respiratory syncytial virusa, Herpes simplex virusb, Epstein–barr virus, Molluscum contagiosumb, Varicella zoster virusa,b	–	–	–	lack of infectionsk	1 respiratory syncytial virus bronchiolitisa	Respiratory syncytial virusa, Human papillomavirusb, Herpes simplex virusb, Epstein–barr virus, Molluscum contagiosumb, Varicella zoster virusa

Site of infection, if known, is indicated by a, lung; b, skin; c, mouth; d, nail; e, kidney; f, eye; g, CNS; h, ear, nose and throat; i, systemic; j, joint; k, pre- and peri-natal death. Epstein–barr virus is associated with lymphoma.

Monoallelic STAT3 mutations cause AD or type 1 HIES (HIES1) [22,23]. Given that HIES1 patients have one wild type and one pathogenic copy of STAT3 one hypothesis is that the pathogenic variant acts as a dominant negative protein resulting in effectively 25% residual STAT3 activity [22]. This model has been recently challenged by a study suggesting that many pathogenic STAT3 variants confer protein instability and that haploinsufficiency with 50% residual STAT3 activity is sufficient to cause disease [24]. However, the direct interference of the variant over the wild type STAT3 was not experimentally confirmed. A more in-depth study reporting a deep intronic splice mutation of STAT3 has demonstrated that the low level of variant (produced between 5% to 20%) showed negative dominance [25]. The similarities of STAT3 defects with the high IgE, eosinophilia, infection susceptibility seen in patients with IL-6R defects suggests that IL-6 plays a key role in the immunological aspects of the disorder [5,6], whereas skeletal abnormalities mirror aspects of IL-11RA defects. In addition, defective signalling in a number of IL-6 family (IL-27) as well as non-IL-6 family cytokines (in particular IL-10, IL-21, IL-22 and IL-23), have been discussed as additional pathogenic components in the HIES mechanism. However, this is not conclusive since defective signalling of these cytokines in isolation does not produce relevant aspects of the HIES phenotype. For example, IL-10 signaling defects cause infantile enterocolitis [26], but despite evidence to suggest that HIES1 macrophages phenocopy IL-10-deficient macrophages, gut inflammation is not a typical feature of HIES [27].

GP130 at the nexus of IL-6 family cytokines

As GP130 is a co-receptor shared by a group of IL-6 family cytokines, its dysregulation has a broad spectrum of effects. Biallelic complete loss-of-function variants of IL6ST that affect all IL-6 family cytokines including LIF cause (an extended) Stüve-Wiedemann syndrome, with additional features of congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response [28]. Infections were not a significant factor, as only one out of five patients from three families with complete absence of GP130 survived the neonatal period, we presume that they did not live long enough to manifest any immuno-deficiency [28].

By contrast, biallelic non-synonymous cytokine-selective loss-of-function variants in IL6ST are a cause of AR HIES, with a clinical presentation of recurrent bacterial skin and lung infections associated with bronchiectasis, eczema, high IgE and eosinophilia, as well as skeletal abnormalities including craniosynostosis. These variants have largely intact LIF signaling but defective IL-6, IL-11, IL-27, and OSM responses [29,30,31]. Patients with partial GP130 deficiency have high arched palate and scoliosis [32] that is seen both in patients with STAT3 [20] or CLC deficiency [11].

Monoallelic dominant-negative IL6ST variants lead to expression of GP130 bearing a truncated intracellular domain that lacks both the recycling motif and all four STAT3 binding sites [32]. Defective internalization causes accumulation of mutant GP130 on the cell surface, and impairment of cellular responses to IL-6 family cytokines [32]. Accumulation of mutant GP130 on the cell surface has a greater effect on hexameric IL-6 and IL-11 receptor complexes that require two intact GP130 chains per complex limiting the number of intact GP130 pairs compared with trimeric LIF receptor complexes that allow each remaining functional GP130 chain to pair with an intact LIF receptor. IL-6 and IL-11 signaling defects are therefore prominent, and LIF signaling is only partially affected.

Similar to IL-6R deficiency [5] but in contrast to AD-HIES [33], Th17 responses were present or modestly reduced in patients with AR and AD IL6ST HIES [29,30,32], and patients do not suffer from chronic mucocutaneous candidiasis. This is consistent with the suggestion that alternative STAT3 inducing cytokines are able to drive Th17 differentiation in the absence of IL-6 signaling [34].

A homozygous non-synonymous variant in IL6ST with selective loss of IL-11 signaling without affecting other GP130-dependent signaling cytokines was identified in a patient with craniosynostosis and retained deciduous teeth [35]. The selective effect on IL-11 signaling shows incomplete penetrance, but phenocopies IL11RA deficiency in humans and mice.

ZNF341 and the transcriptional control of STAT3

Biallelic variants in ZNF341, encoding a zinc-finger transcription factor that binds the STAT3 promotor and regulates STAT3 transcription (Figure 2), present with staphylococcal infections, severe allergy, and high serum IgE levels in a AR mode of inheritance. As a consequence of defective STAT3 transcriptional control, these patients show reduced transcriptional activitiy in primary fibroblasts, B cells and CD4 + T cells, reduced STAT3 phosphorylation, impaired Th17 differentiation, and a skewed Th2 phenotype [36,37]. In comparison with STAT3-HIES patients, there are fewer extra-hematopoietic manifestations.

Figure 2

Genetic causes of hyper-IgE syndrome in a cellular disease state network.

Key aspects of hyper-IgE syndrome are caused by defective IL-6 and IL-11 signalling. This can be caused by a defective receptor complex (AR IL6ST, IL6R) as well as defective STAT3 activation and DNA binding activity (AD STAT3). Defects in the GP130 endosomal uptake cause accumulation of truncated signalling defective GP130 variants (AD IL6ST) at the cell membrane, whereas defects in PGM3 cause defective GP130 glycosylation and surface expression. Defects in ZNF341 cause defective STAT3 transcriptional control. A role of non-canonical STAT3 signalling is suggested by the phenotype of patients with defects in ERBIN that affect the STAT3-ERBIN-SMAD2/3 complex as well as TGF-β receptor 1 and 2 defects.

Defective glycosylation of GP130 due to PGM3 defects

Patients with biallelic loss-of-function variants in phosphoglucomutase 3 (PGM3), present with an AR disorder including several features of classical HIES including increased serum IgE levels, recurrent skin and pulmonary infections, abscesses and bronchiectasis [38, 39, 40]. This can be partially explained by defective glycosylation of GP130 in theses patients causing lower GP130 surface expression and impaired STAT3 activation [41] (Figure 2). However, defective glycosylation of GP130 is likely only one aspect of the PGM3 associated pathology.

Defective control of TGF-β signaling due to defects in STAT3-ERBIN-SMAD2/3 complex

It is not clear why impaired IL-6/STAT3 signaling leads to immunological features such as high IgE and why impaired IL-11/STAT3 signalling should lead to connective tissue defects. Key for understanding might be the intersection with non-canonical STAT3 signalling pathways. Patients with ERBIN deficiency and Loeys–Dietz-syndrome due to TGF-β receptor defects show elevated IgE (ERBIN-deficient patients show only slightly elevated serum IgE), eosinophilic inflammation, joint hypermobility and vascular abnormalities [42,43]. Patients with mutations in ERBB2IP demonstrated reduced expression of ERBIN, impaired formation of the STAT3–ERBIN–SMAD2/3 complex and failure to constrain TGF-β signaling. This deregulated TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes, and increased activation of the IL-4-GATA3 axis in vitro [42]. This is corroborated by the detection of increased IL4R expression in naïve lymphocytes in IL6R deficiency [5].

Other immunodeficiencies associated with elevated IgE

In addition to those immune defects that affect IL-6 family cytokines directly or indirectly, there are multiple other genetic defects that cause raised IgE levels, but present with a distinct phenotype from the immune disorders associated with impaired IL-6 family cytokine signaling and likely have a different mechanism. For instance, patients with biallelic loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) present with a AR form of HIES characterized by frequent recurrent cutaneous viral infections, an increased incidence in allergic responses [44] but lack the skeletal defects. Similarly, the majority of patients with TYK2 defects, one of the three JAKs associated with GP130 signaling, present with defects in type I antiviral and mycobacterial immunity and not HIES indicating that TYK2 deficiency is key for type 1 IFN and IL-23 signalling and less relevant for GP130-STAT3 signaling [45,46].

Inborn errors with gain-of-function in the GP130-STAT3 pathway

In addition to the large group of inborn errors with loss-of-function, there are also gain-of-function variants in IL6ST and STAT3. De novo gain-of-function STAT3 variants are associated with immune dysregulation, lymphoproliferation, enteropathy and short stature [47,48]. Although many patients do not present with infection susceptibility, there are case reports of mycobacterial disease [49]. A similar phenotype was seen in a de novo and mosaic IL6ST variant inducing constitutive GP130 cytokine signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy [50]. In STAT3 gain-of-function patients there has been some success in the use of JAK inhibitors to treat the inflammatory disease [48].

IL-6 family cytokines — beyond rare inherited disorders

In addition to rare patients with inborn errors of IL-6 family signaling, there are multiple additional layers of evidence that highlight the role of IL-6 family cytokines in the pathogenesis and treatment of immune-mediated diseases. Common risk variants identified by genome-wide association studies also reveal potential pathways that contribute to disease pathogenesis. For instance, population genetic studies identified common variations in the IL6R gene that conferred susceptibility to atopic dermatitis and asthma [51, 52, 53]. IL6ST variants have been associated with multiple sclerosis and rheumatoid arthritis [54]. Tocilizumab, a humanized monoclonal antibody targeting IL-6R, is licensed to treat an expanding list of inflammatory conditions including rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome associated with chimeric antigen receptor T cell therapy [55]. An anti-IL-6 antibody had acceptable benefit/risk profile in Crohn’s disease patients who failed infliximab [56]. Inhibition of IL-6 trans-signalling in patients with active inflammatory bowel disease via soluble gp130Fc olamkicept may have therapeutic effects [57]. Tocilizumab was associated with improved survival in critically ill COVID-19 patients admitted to hospitals in some but not all studies [58, 59, 60, 61]. Among the other cytokines in the IL-6 family, blockade of IL-11 has been shown to have potential therapeutic effects in idiopathic pulmonary fibrosis [62]. High levels of OSM expression seen in the intestinal mucosa and plasma of Inflammatory bowel disease patients correlate with histopathological disease severity and failure to respond to anti-TNF therapy [63] suggesting that understanding OSM biology might have diagnostic or therapeutic implications.

Essential functional pathways are furthermore highlighted by similarities in the infection susceptibility in patients with Mendelian disorders and patients with anti-cytokine autoantibodies and adverse effects to therapeutic interventions. Several case reports indicate severe bacterial infections in the absence of an acute phase response in patients who developed anti-IL-6 autoantibodies [64,65]. Similarly, patients with tocilizumab are at increased risk for serious invasive bacterial infections as well as skin and soft tissue infections [66]. Another less common but severe phenotype observed in Mendelian disorders and treatments that target IL-6 signalling pathway is intestinal perforation. Gastrointestinal perforation was reported in ten STAT3 AD-HIES patients and there is an increased risk of gastrointestinal perforation in rheumatoid arthritis patients treated with tocilizumab [67]. Thrombocytopenia, a clinical feature seen in patients with OSM and complete loss-of-function GP130 defects, has been noted in a phase I study of individuals who received anti-OSM antibodies [68].

However, not all phenotypic features of Mendelian disorders are reflected by therapeutic interventions. It is intriguing that congenital defects in IL-6 signaling cause infantile immunopathology associated with high IgE, whereas therapeutic targeting of IL-6 signalling does not. This is likely due to quantitative differences between complete loss-of-function genetic defects and the incomplete blockade of signalling pathways achieved by medications. On the other hand this is potentially due to developmental aspects and it will be important to see the long-term response of infants exposed to anti-IL-6 targeting therapies [69].

Conclusions

The study of patients with inborn errors in IL-6 family cytokine signalling helps to delineate the relative contributions of individual cytokines. Pathogenic variants both in IL6R and IL6ST phenocopy the immunodeficiency of classical HIES due to STAT3 variants. All three are charecterized by bacterial and fungal infections that particularly affect the skin and lungs. Current data highlight the role of IL-6 for the immunodeficiency seen in HIES and excludes a significant role for the other members of the GP130 cytokine family. Impaired Th17 responses were initially seen as an explanation for the pattern of infections seen in HIES [33], however Th17 cells are seen in patients with IL6ST mutations suggesting that defective IL-6 driven signals can be overcome by IL-1 and IL-23 stimulation. Loss of IL-6 signaling affects the acute phase protein secretion which may contribute to the distictive pattern of infections seen in these patients. It is notable that patients with IL-11RA or OSMR deficiency do not have a specific pattern of infections.

Understanding the combinatorial biology will help to develop targeted therapies, predict and understand adverse outcomes of therapies and to predict the phenotypes of not yet identified biallelic deficiencies (such as IL-6 and IL-11 loss-of-function defects). In light of the complex infection susceptibility of IL-27 deficient model systems, it will be interesting to see whether defective IL-27 signalling in humans would cause a specific immune phenotype.

Conflict of interest statement

H.H.U. has received research support or consultancy fees from Janssen, UCB Pharma, Eli Lilly, , ,Celgene/, MiroBio, and . H.H.U., A.L. and Y.-H.C. are supported by a research collaboration with BMS.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest