Candidate Genetic and Molecular Drivers of Dysregulated Adaptive Immune Responses After Traumatic Brain Injury

Abstract

Neuroinflammation is a significant and modifiable cause of secondary injury after traumatic brain injury (TBI), driven by both central and peripheral immune responses. A substantial proportion of outcome after TBI is genetically mediated, with an estimated heritability effect of around 26%, but because of the comparatively small datasets currently available, the individual drivers of this genetic effect have not been well delineated. A hypothesis-driven approach to analyzing genome-wide association study (GWAS) datasets reduces the burden of multiplicity testing and allows variants with a high prior biological probability of effect to be identified where sample size is insufficient to withstand data-driven approaches. Adaptive immune responses show substantial genetically mediated heterogeneity and are well established as a genetic source of risk for numerous disease states; importantly, HLA class II has been specifically identified as a locus of interest in the largest TBI GWAS study to date, highlighting the importance of genetic variance in adaptive immune responses after TBI. In this review article we identify and discuss adaptive immune system genes that are known to confer strong risk effects for human disease, with the dual intentions of drawing attention to this area of immunobiology, which, despite its importance to the field, remains under-investigated in TBI and presenting high-yield testable hypotheses for application to TBI GWAS datasets.

Introduction

Traumatic brain injury (TBI) is a major cause of morbidity and death worldwide, with an estimated 70 million cases annually.¹ Secondary injury (additional brain injury caused by downstream processes triggered by the initial mechanical trauma) is thought to be a substantial and potentially preventable determinant of outcome after TBI, with only approximately one third of outcome variability being currently explained by initial injury and patient factors.^2,3 Neuroinflammation is a key component of secondary injury in the acute phase, occurring via both direct glial responses to injury and indirect responses to systemic inflammation, and is also thought to contribute to chronic neurodegeneration post-TBI.⁴ While most neurotrauma research has focused on the innate arm of the immune system, it is increasingly recognized that adaptive immune responses, including trauma-induced autoimmunity, play an important role through either the beneficial clearance of cell debris or destructive autoimmune damage.^5,6

The immune system displays great heterogeneity between individuals, with genetic factors representing significant determinants in the host response to infection, cancer, and the development of immunological diseases.^7
–9

While autoimmune diseases are often individually rare, it is estimated that up to 8% of the population are affected by autoimmune disease,¹⁰ and therefore the genetic predisposition toward autoimmunity is even more common. Given the high frequency of genetic variants affecting the immune response, it is likely that these contribute to the heterogeneity in immune response seen after TBI and may in turn represent determinants of outcome.

The largest genome-wide association study (GWAS) in TBI (n = 5268) has recently been reported and estimates that 26% of outcome variation is genetically mediated, but was not able to demonstrate any specific variants that met the genome-wide threshold of significance (p < 5 × 10⁻⁸).¹¹ The nature of unbiased data-driven approaches to GWAS data is that extremely large datasets are needed to identify true signals after accounting for the multiplicity of testing. This is a significant issue even in “straight-forward” binary scenarios such as comparing patients with a disease and healthy controls, let alone when looking for effects on outcome in a disease as heterogeneous as TBI.

An alternative approach, which substantially reduces the burden of multiple comparisons, is to apply a hypothesis-driven candidate gene approach to the dataset, based on pre-determined biological hypotheses. We hypothesise that genetic variants that are known risk factors for autoimmunity are likely to also predispose to the loss of immunological self-tolerance after TBI and would therefore predict worse outcome; indeed one of the few loci of interest reported by the recent TBI GWAS was Human Leukocye Antigen HLA-DQB1,¹¹ which is implicated in a number of autoimmune diseases including those of the central nervous system (CNS).¹²

In this review, we identify genes that are most frequently recognized as risk factors for autoimmunity from GWAS of several immune-mediated disorders and discuss how variants affecting these genes may be biologically relevant in post-TBI autoimmunity and should therefore be investigated independently within GWAS datasets.

Methods

Lists of GWAS for eight common autoimmune conditions and the relevant associated single nucleotide polymorphisms (SNP)/genes were extracted from the NHGRI-EBI GWAS Catalog.¹³ These conditions were Crohn disease, ulcerative colitis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, and celiac disease. The top 20 genes that were implicated most frequently across these eight conditions were identified (Table 1).

Table 1.

Genes Commonly Implicated in Association Studies Across Multiple Autoimmune Disorders

HLA Family	BACH2	CTLA4	IL-2RA	CD28
IL-21	SH2B3	STAT4	TYK2	ETS1
IKZF3	IL-10	IL-12B	IL-2	IRF5
PTPN2	PTPN22	PUS10	TAGAP	TNFAIP3

A Python script was written to distill relevant information regarding each gene from PubMed MEDLINE for inclusion in this review (Fig. 1). This script used three parameters: [GENE NAME], phrase [IMMUNE], and list of each [DISEASE(s)] used earlier. It then performed individual searches for all listed [DISEASE(s)] and after comparison, produced a list of publications that were repeated between the searches.

FIG. 1.

Illustration of the search strategy. The NHGRI-EBI Catalogue was searched, and data extracted manually for genes associated with eight autoimmune conditions (CD Crohn Disease, UC–Ulcerative Colitis, SLE–Systemic Lupus Erythematosus, RA–Rheumatoid Arthritis, MS–Multiple Sclerosis, T1DM–Type 1 Diabetes Mellitus, ATD–Autoimmune Thyroid Disease, CeD–Celiac Disease). Literature relevant to the top 20 most frequently associated genes were then reviewed using a Python script sifting through Pubmed database and comparing lists of PMIDs produced by the [GENE] [IMMUNE] [DISEASE] query. [GENE]–currently investigated gene, [IMMUNE]–fixed element of the query, [DISEASE]–investigated disease. This initial query produced 13,899 articles. For each gene, an additional search with the query [GENE] [IMMUNE] [BRAIN] was performed. Lists of PMIDs for each gene and each disease were created, and inside one gene group compared between themselves (including the [BRAIN] query). If a PMID repeated once, it was added onto the “Appear in two searches” list. If it appeared more than twice it was added onto the “Appear in more than two searches” list. Both lists were reviewed manually for the final selection of articles to be discussed in the review.

After this, publications produced by [GENE NAME][DISEASE(s)][BRAIN] or [BRAIN INJURY] were added to each list. The search resulted in two lists of publications: those appearing in two searches, and those that appear in more than two. This helped identify key publications as well as bring attention to ones for further exploration.

Results and Discussion

Risk loci for autoimmunity can be broadly categorised into five main areas: HLA type, regulators of lymphocyte activation, cytokines and their receptors, transcription factors and related modulators of gene expression, and intracellular signaling pathways. These are presented in Figure 2, and discussed below in turn.

FIG. 2.

(1) Intracellular enzymes and adaptor proteins and transcription factors placed on a spectrum according to their contribution toward T-effector cell or T-regulatory cell differentiation. (2) CD28 provides the second signal to activate T-cells. In moderate activation it promotes T-effector expansion and promotes autoimmunity. When strongly activated it promotes T-reg differentiation and has a regulatory role. CTLA4 competes with CD28 for CD80/86 ligand and protects against autoimmunity. (3) Interleukin (IL)-10 is the main immunosuppressive cytokine secreted post-traumatic brain injury (TBI) by B-reg and T-reg cells. IL-2 is necessary for both T-reg and T-effector cell expansion, and impairment of signaling impairs mainly T-reg cell differentiation and promotes autoimmunity. IL-21 promotes T-effector cell differentiation and action while inhibiting that of T-reg cells; it is also a key regulator of germinal B-cell differentiation. IL12B is a component of the proinflammatory IL23 cytokine that strongly activates Th17 responses. (4) MHC I molecule expression is induced in neurons and microglia post-TBI; mutations leading to an increase in MHC II promiscuity are often associated with greater post-TBI autoimmunity risk.

HLA–Major Histocmopatibility Complex (MHC) Class 1 and 2

The MHC class II molecule is responsible for recognizing and presenting extracellular antigens to immune cells of the adaptive immune system (namely T-cells) and represents the largest source of genetic predisposition to autoimmune disease.¹⁴ Further, the effect size of risk conferred by MHC II variants can be substantial (e.g., an odds ratio of more than 7 for HLA-DQA1 in celiac disease).¹⁵

The MHC II is expressed by glia within the CNS and is required for the trafficking of self-reactive T-cells into the CNS and subsequent generation of autoimmune neurological diseases such as MS.¹⁶ The MHC II is significantly upregulated in the brain after TBI in mice, with a notable variation between genetically different strains, and leads to significant T-cell influx in this context.¹⁷

The MHC II polymorphisms are also implicated in autoimmune neurological disease that arises from outside the CNS; LGI1 and CASPR2 encephalitides are conditions with strong MHC II allelic associations that are characterized by the production of autoantibodies within the peripheral compartment that then enter the CNS to cause neuroinflammation.¹⁶

Given its function, MHC II is likely to be involved in the initiation of both the cellular and humoral adaptive immune responses against released neural antigens seen in the peripheral compartment after TBI.^18
–20 Particular mutations increasing promiscuity of the receptor—i.e., in the DQ²¹ or in DR molecule^22,23 —may increase the likelihood for self-recognition, and indeed HLA-DQB1 was identified in the TBI GWAS study as a locus of interest at the subgenome-wide level of significance.¹¹

The MHC type I is expressed by all nucleated cells of the body and is responsible for the presentation of both self and non-self intracellular antigens.²⁴ Response to presented self-antigens is usually inhibited by both central and peripheral tolerance mechanisms.²⁵ Even though less frequently associated with autoimmune disease, several haplotypes that strongly predispose to certain autoimmune disease have been identified, with perhaps the most well-established of these being HLA-B27 and ankylosing spondylitis.²⁶ Introduction of human HLA-B27 and β2 microglobulin genes into rats precipitates an inflammatory disease strikingly similar to HLA-B27-associated disease in humans, highlighting the magnitude of effect that HLA-type can infer.²⁷

While there is less evidence of the role of MHC I in neuroinflammatory disease, sustained exposure to interferon gamma (as is seen in TBI) leads to upregulation of MHC I on neurons, with subsequent antigen-specific cytotoxic T-lymphocyte mediated neuronal destruction.²⁸ Further, upregulation of MHC I antigen processing and presentation pathways is seen in glial cells after TBI, raising the possibility that a similar process might lead to glial injury.²⁹

T-cell activation–CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)

A CD28 is a receptor for CD80/86 and a major costimulatory molecule for the activation of T-cells, lying in close genetic approximation with CTLA4 on chromosome 2,³⁰ meaning that many SNPs in the CD28 and CTLA4 genes show linkage disequilibrium.³¹ Combined CD28 and CD3 stimulation in the presence of self-antigen presentation may be used to experimentally induce autoimmune conditions; CD28 knockout mice are relatively protected against autoimmune disease,³² and T-cells from CD28 knockout mice fail to migrate and infiltrate tissues in experimental autoimmune encephalomyelitis.³³

The CD28 super-agonist induced T-reg expansion, however, limits brain damage in an experimental model of stroke in mice,³⁴ pointing to a dual role of CD28-CD80/86 signaling by both promoting tolerance by T-reg expansion and aggravating autoimmunity by T-effector stimulation.

The CTLA4 is an immunosuppressive molecule with high-affinity for its ligands CD80 and CD86. It is constitutively expressed by regulatory T-cells and upregulated on activation of T-cells in a homeostatic manner, acting to prevent unbridled T-cell activation.³⁵ In a dramatic genetic example of its function, multifaceted autoimmune disease with large CNS lesions develops in haploinsufficient patients, demonstrating how loss-of-function mutations can predispose to autoimmunity.³⁶

Association studies have implicated variants in the CD28/CTLA4 locus with a wide array of autoimmune disease including T1DM, autoimmune thyroid disease, SLE, and MS.^37,35 Although the effect size of risk alleles is small, they have a high frequency within the population.^38,39

Therapeutically harnessing the effects of CTLA4 can significantly ameliorate neuroinflammation^40,41 and therefore might represent a tractable target in TBI. Further, it has been shown to promote neuronal stem cell survival and differentiation and therefore genetic variants might have downstream effects on repair mechanisms post-TBI.^42
–44

Cytokines–interleukin (IL)-2, IL-2RA, IL-10, IL-12B, and IL-21

Cytokine-related genes are recognized risk loci for a number of autoimmune diseases, and indeed there is support in the literature for SNPs in IL-1β and tumor necrosis factor (TNF)α associating with unfavorable outcomes post-TBI.^45,46

Regulatory T-cells constitutively express the IL-2 receptor and are dependent on IL-2 for their development and function.⁴⁷ The IL-2 is therefore considered a potent anti-inflammatory cytokine, and polymorphisms relating to IL-2 and its receptor have been implicated in autoimmune disease including T1DM, RA, and MS.⁴⁸ IL-2 gene knockout in mice leads to systemic autoimmune disease, but also to increased migration of T-cells into the brain.⁴⁹

After TBI, IL-2 concentrations within the CNS drop to a level where regulatory T-cells cannot survive, and rectifying this deficit significantly reduces lesion size in a mouse model.⁵⁰ Despite being broadly regarded as an anti-inflammatory cytokine, in high concentrations IL-2 can drive effector cell activation and therefore inflammation,⁵¹ as well as promoting blood-brain barrier disruption, thus allowing immune cells and autoantibodies to enter the brain parenchyma,⁵² highlighting the importance of tight regulation.

The IL-10 is the main immunosuppressive cytokine produced by T-regs, B-regs, and monocytes. In B-cell deficient mice, IL-10 introduction significantly limits post-stroke CNS inflammation and increased T-reg populations.^53,54 Circulating IL-10 levels surge after TBI, in turn suppressing astrocytic production of pro-inflammatory IL-6 in response to IL-1β released from injured brain tissue.⁵⁵ In addition, IL-10 improves neuronal survival after axotomy and limits microglial inflammatory responses.⁵⁶

It may thus be speculated that post-TBI IL-10-mediated immune suppression is a natural mechanism protecting the CNS from inflammation. The IL-10 secreting B-reg populations decrease after TBI, however, and pneumonia developed in patients with high levels of these cells on day 1 after TBI.⁵⁷ The IL-10 may be both protective against post-TBI autoimmunity but also be the cause for poor patient outcomes from infection, highlighting the competing interests between compartments.

The IL-12B encodes the IL-12p40 subunit, which is a component of both IL-12 and IL-23, the latter of which is a potent driver of the Th17 responses that are so characteristic of many autoimmune conditions.⁵⁸ Variants such as V298F mutation impair IL-12 and IL-23 assembly and in turn decrease immune activation and risk of autoimmunity.⁵⁹

Although not essential for autoimmunity development, IL-21 promotes CD8+ T-cell response toward low-affinity (i.e., self) ligands and is a key driver of germinal center development and maintenance.^60
–62 It enhances Th17 proliferation and inhibits that of T-regs.^63,64 BITRAP, a fusion protein targeted at both TNF-α and IL-21, successfully decreased Th17 numbers and increased IL-10 levels in vitro. ⁶⁵ In MS lesions, IL-21 is expressed by CD4+ infiltrating T-cells and from neurons that expressed IL-21R as well, suggesting an additional mechanism of inflammation maintenance.⁶⁶ The IL-21 producing T-cells have also been implicated as key players in several different non-neurological autoimmune conditions.^67
–69

Transcription factors and other regulators of gene expression

Mutations in a number of transcription factors have been implicated in autoimmunity, with certain loss-of-function mutations causing frank syndromic autoimmune disease such as FOXP3 leading to the Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome (IPEX), and AIRE causing Autoimmune Polyglandular Syndrome type 1.⁷⁰ Four transcription factors have been strongly implicated across a number of autoimmune diseases including SLE, RA, inflammatory bowel disease, and MS: ETS1, IKZF3, IRF5 and BACH2.^71

–76 The IRF5 raises particular interest, given that a relatively high risk for SLE (odds ratio 1.45) is conferred by the rs4728142 SNP, which is found commonly in the population with a high allelic frequency.⁷⁷

Broadly speaking, these transcription factors either promote proinflammatory functions of immune cells, or mediate regulatory countermeasures. The ETS1 is widely expressed on both T and B lymphocytes and promotes IL-2 expression with subsequent effects on regulatory T-cells, suppression of Th17 cell expansion, and autoimmunity development;^78,79 a SLE-like syndrome develops in knockout models.⁸⁰

The IKZF3 encodes the protein Aiolos, which is a key transcription factor for B-cell proliferation and differentiation,⁸¹ a mediator of innate NK and ILC1 responses,⁸² and a promoter of Th-17 differentiation via suppression of IL-2 synthesis.⁸³

Interferon regulatory factor 5, encoded by the IRF5 gene drives macrophages toward a proinflammatory phenotype, modulates B-cell maturation and antibody production, and pushes T-lymphocytes toward Th1 and Th17 differentiation.^84,85,75 Of note, upregulation of the expression of type 1 interferon signaling pathway genes including regulatory factors such as IFR5 have been demonstrated in microglia after TBI⁸⁶ and particularly in aged mice,^87,88 suggesting an additional important inflammaging effect.

Further, inhibiting these pathways seems to be beneficial, with Interferon-β knockout mice displaying reduced neuroinflammation and better pathological and functional outcomes after TBI, and treatment with anti-type 1 interferon antibodies transiently improving functional outcome. ⁸⁹

BACH2 is a transcription factor acting on the JAK/STAT pathway that restricts terminal T-helper cell differentiation and is essential for efficient T-reg formation.^90,91 Mice deficient for Bach2 on T-lymphocytes showed abnormal Tfh proliferation and development of humoral autoimmunity.⁹²

In addition to mutations in transcription factors themselves, both upstream and downstream modulators of gene expression have similarly been recognized to infer risk of autoimmunity. The TNFAIP3 product A20 is rapidly induced by TNF⁹³ and acts as a potent inhibitor of the NFκB pathway,⁹⁴ protecting against unbridled inflammation and autoimmune responses. A20 deficiency in mice results in increased number of B-cell germinal centres and raised autoantibody titres.⁹⁵

Three SNPs (rs13192841, rs2230926 and rs6922466) have been associated with increased susceptibility to RA and SLE (some with large effect sizes), suggesting a wider overall role of TNFAIP3 in autoimmune disease.⁹⁶ Injection of A20 into RA mice showed significant NFκB signaling reduction and amelioration of the disease phenotype.⁹⁷ In MS, A20 is reduced at disease onset.⁹⁸ Further, A20 has been shown to inhibit necroptosis and therefore may serve a broader role as a neuroprotective agent in post-TBI damage;⁹⁹ silencing of A20 leads to significantly increased necroptosis after TBI via its inhibitory effect on the TNF-mediated downstream RIP1/RIP3-MLKL signaling pathway, as well exacerbating neuroinflammation (both as a result of the increased necroptosis and its more classic effects on the NFκB pathway).¹⁰⁰

The PUS10 is a ubiquitous enzyme, which acts predominantly by promoting microribonucleic acid (mRNA) biogenesis and post-transcriptional regulation of gene expression.¹⁰¹ It is essential for TRAIL-induced apoptosis progression, and mutations are associated with cell immortality and better proliferation,^102,103 contributing to “immortalization” of autoimmune effector cells.

Intracellular signaling

The PTPN2 and PTPN22 genes encode non-receptor protein tyrosine phosphatases, and have both been reproducibly identified as common risk loci for autoimmune disease,^104,105 with a comparatively high frequency of risk alleles in the population.^106,107

The PTPN2 expression induces regulatory T-cells, encourages differentiation away from Th1/17 phenotypes, reduces responsiveness to interferon-γ, and inhibits autophagy. Loss-of-function mutations show aggravated NOD-2 responses to bacterial recognition and subsequent Crohn disease development.¹⁰⁸ The PTPN2 deficient T-cells precipitate widespread autoimmunity that is transferrable by CD8+ T-cell transfer to wild-type mice,¹⁰⁹ and humoral autoimmunity develops in knockout mice.¹¹⁰

The PTPN22 is one of the better established non-HLA risk factors for autoimmune disease. It effects a potent inhibitory influence, predominantly at the T-cell receptor, by dephosphorylating a number of key kinases at their activation loop tyrosines.¹¹¹ The R620W (C1858T) gain-of-function mutation infers a significantly increased risk for a range of autoimmune conditions such as T1DM and RA,¹¹² and importantly this gain-of-function polymorphism has a high frequency in the population (up to 15.5% in some countries),¹¹³ identifying it as a high yield gene to study in TBI. Further, given its limited expression outside immune cells, it is a promising target for treatment—e.g., with short interfering RNA because off-target effects are likely to be minimal.^114,115

The SH2B3, known as the Lnk adaptor protein, is expressed mainly in lymphoid tissues. Loss-of-function mutations lead to increased susceptibility to autoimmunity and acute lymphoblastic leukemia, and the rs3184504 SNP predisposes to a number of autoimmune conditions.¹¹⁶ An SH2B3 deficiency results in heightened number and responsiveness of DCs and inflammatory CD8+ T-cells in affected mice.^117,118 Of particular interest is the association of the rs3184504 SNP with reduced death in sepsis,¹¹⁹ again raising the notion that a predisposition to autoimmunity in critical illness is not necessarily detrimental and may be protective.

The TAGAP is a small GTPase activating protein, key in the regulation of Th17 differentiation. In TAGAP-deficient mice, fungal infections develop but mice are partially protected from MS.¹²⁰ The STAT4 is phosphorylated by Janus kinases and transduces signals from IL-12, IL-23, and IFNγ. The Th2 cells show decreased levels of STAT4, and artificial induction of this protein leads to a Th1-like repolarization of these cells.^121,122 It suppresses T-reg differentiation, and when knocked out can lead to their increased proliferation and prevention of experimental colitis in mice.¹²³

The TYK2 belongs to the Janus kinase family; thus it can signal via STAT pathways. Its deactivation via IFN-β action leads to better outcomes in patients with MS.¹²⁴ Small biological TYK-2 inhibitors proved to be useful in IL-12 and IL-23 cytokine signaling pathway dampening and may be efficacious in managing selective autoimmune conditions.¹²⁵

Conclusion

Approximately 26% of variation in TBI outcome is thought to be genetically mediated, but studies using purely data-driven analysis approaches have yet to identify crucial predisposing variants. In a disease as complex as TBI, applying hypothesis-driven approaches to datasets offers a chance to identify risk variants by using an understanding of the biology of TBI to highlight candidate genes (Table 1), and therefore limit the volume of data analyzed.

Adaptive immune responses to TBI represent an important, therapeutically modifiable part of the disease process, and heterogeneity in adaptive immune responses has a well-documented genetic basis. By focusing on genes that are known to have significant effects on predisposition toward autoimmunity, either through the strong effect of an uncommon variant or the combined weak effects of common variants, it may be possible to identify important genetic drivers of TBI outcome, and in due course novel treatment targets; looking to the future, the advent of personalized medicine will rely heavily on rapid genotyping to inform an individual's treatment regimen, and tailoring immunomodulatory treatments by genotype will optimize efficacy and safety.

This review identifies candidate genes that may be likely to confer effects on post-traumatic autoimmunity as a framework on which to base hypothesis-driven analysis of current and future GWAS data in TBI.

Footnotes

Acknowledgments

Figure 1 was created using https://app.diagrams.net/. was created with BioRender.com.

Author's Contributions

MD and JL performed the literature search and drafted the manuscript. EN devised the manuscript concept, and supervised the manuscript drafting. DM revised the manuscript.

Funding Information

EJN and DKM are supported by the Medical Research Council (UK) within the framework of ERA-NET NEURON, and by Brain Research UK.

DKM is supported by an NIHR Senior Investigator Award and European Union 7th Framework program (EC grant 602150).

Author Disclosure Statement

MD, JL, and EN have no disclosures.

DKM reports grants, personal fees, and nonfinancial support from GlaxoSmithKline Ltd.; grants, personal fees, and other from NeuroTrauma Sciences; grants and personal fees from Integra Life Sciences; personal fees from Pfizer Ltd.; grants and personal fees from Lantmannen AB; from Calico Ltd.; personal fees from Pressura Neuro Ltd.; and others from Cortirio Ltd., outside the submitted work.

References

Dewan

, Rattani

, Gupta

, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg, 2018; 1–18; doi: 10.3171/2017.10.JNS17352

Meyfroidt

, Bouzat

, Casaer

, et al. Management of moderate to severe traumatic brain injury: an update for the intensivist. Intensive Care Med, 2022; 48(6):649–666; doi: 10.1007/s00134-022-06702-4

Lingsma

, Roozenbeek

, Steyerberg

, et al. Early prognosis in traumatic brain injury: from prophecies to predictions. The Lancet Neurol, 2010; 9(5):543–554; doi: 10.1016/S1474-4422(10)70065-X

Faden

, Loane

. Chronic Neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?. Neurotherapeutics, 2015; 12(1):143–150; doi: 10.1007/s13311-014-0319-5

Javidi

, Magnus

. Autoimmunity after ischemic stroke and brain injury. Front Immunol, 2019; 10:686; doi: 10.3389/fimmu.2019.00686

Needham

, Helmy

, Zanier

, et al. The immunological response to traumatic brain injury. J Neuroimmunol, 2019; 332:112–125; doi: 10.1016/j.jneuroim.2019.04.005

Ramos

, Shedlock

, Langefeld

. Genetics of autoimmune diseases: insights from population genetics. J Hum Genet, 2015; 60(11):657–664; doi: 10.1038/jhg.2015.94

Gibbs

, Schott

, Ko

. The awesome power of human genetics of infectious disease. Annu Rev Genet, 2022; 56(1):41–62; doi: 10.1146/annurev-genet-080320-010449

Evans

. Genetic predisposition to cancer. Medicine, 2016; 44(1):65–68; doi: 10.1016/j.mpmed.2015.10.003

10.

Committee

ADC

, others. NIH Publication 05-5140. Bethesda, MD: The Autoimmune Diseases Coordinating Committee, National Institute of Allergy and Infectious Diseases, National Institutes of Health; 2005.Progress in Autoimmune Disease Research. Report to Congress. n.d. [Last accessed Apr 27, 2011]. PLEASE ADD HTTP, ETC.

11.

Kals

, Kunzmann

, Parodi

, et al. A genome-wide association study of outcome from traumatic brain injury. eBioMedicine, 2022; 77:103933; doi: 10.1016/j.ebiom.2022.103933

12.

Muñiz-Castrillo

, Vogrig

, Honnorat

. Associations between HLA and autoimmune neurological diseases with autoantibodies. Autoimmun Highlights, 2020; 11(1):2; doi: 10.1186/s13317-019-0124-6

13.

Buniello

, MacArthur

JAL

, Cerezo

, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res, 2019; 47(D1):D1005–D1012; doi: 10.1093/nar/gky1120

14.

Dendrou

, Petersen

, Rossjohn

, et al. HLA variation and disease. Nat Rev Immunol, 2018; 18(5):325–339; doi: 10.1038/nri.2017.143

15.

van Heel

, Franke

, Hunt

, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet, 2007; 39(7):827–829; doi: 10.1038/ng2058

16.

Binks

, Varley

, Lee

, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain, 2018; 141(8):2263–2271; doi: 10.1093/brain/awy109

17.

Al Nimer

, Beyeen

, Lindblom

, et al. Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury. Brain Behav Immun, 2011; 25(5):981–990; doi: 10.1016/j.bbi.2010.10.017

18.

Needham

, Stoevesandt

, Thelin

, et al. Complex autoantibody responses occur following moderate to severe traumatic brain injury. J Immunol, 2021; 207(1):90–100; doi: 10.4049/jimmunol.2001309

19.

Zhang

, Zoltewicz

, Mondello

, et al. Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products. Cohen IR. ed. PLoS ONE, 2014; 9(3):e92698; doi: 10.1371/journal.pone.0092698

20.

Cox

, Coles

, Nortje

, et al. An investigation of auto-reactivity after head injury. Journal of Neuroimmunology, 2006; 174(1–2):180–186; doi: 10.1016/j.jneuroim.2006.01.007

21.

Pavelko

, Drescher

, McGavern

, et al. HLA-DQ polymorphism influences progression of demyelination and neurologic deficits in a viral model of multiple sclerosis. Mol Cell Neurosci, 2000; 15(6):495–509; doi: 10.1006/mcne.2000.0843

22.

Goyette

, Boucher

, Mallon

, et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet, 2015; 47(2):172–179; doi: 10.1038/ng.3176

23.

Hendrickx

DAE

, van Eden

, Schuurman

, et al. Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology. J Neuroimmunol, 2017; 309:12–22; doi: 10.1016/j.jneuroim.2017.04.007

24.

Rock

, Reits

, Neefjes

. Present Yourself! By MHC Class I and MHC Class II Molecules. Trends Immunol, 2016; 37(11):724–737; doi: 10.1016/j.it.2016.08.010

25.

Alpdogan

, van den Brink

MRM

. Immune tolerance and transplantation. Semin Oncol, 2012; 39(6):629–642; doi: 10.1053/j.seminoncol.2012.10.001

26.

Chen

, Li

, He

, et al. Role of HLA-B27 in the pathogenesis of ankylosing spondylitis. Mol Med Rep, 2017; 15(4):1943–1951; doi: 10.3892/mmr.2017.6248

27.

Hammer

, Maika

, Richardson

, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: An animal model of HLA-B27-associated human disorders. Cell, 1990; 63(5):1099–1112; doi: 10.1016/0092-8674(90)90512-D

28.

Sauer

, Schmalstieg

, Howe

. Axons are injured by antigen-specific CD8+ T cells through a MHC class I- and granzyme B-dependent mechanism. Neurobiol Dis, 2013; 59:194–205; doi: 10.1016/j.nbd.2013.07.010

29.

Todd

, Chimenti

, Luo

, et al. Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response. J Neuroinflammation, 2021; 18(1):151; doi: 10.1186/s12974-021-02197-w

30.

Butty

, Roy

, Sabeti

, et al. Signatures of strong population differentiation shape extended haplotypes across the human CD28 , CTLA4 , and ICOS costimulatory genes. Proc Natl Acad Sci USA, 2007; 104(2):570–575; doi: 10.1073/pnas.0610124104

31.

Liaskou

, Jeffery

, Chanouzas

, et al. Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals. Sci Rep, 2017; 7(1):7652; doi: 10.1038/s41598-017-07967-2

32.

Bachmaier

, Pummerer

, Shahinian

, et al. Induction of autoimmunity in the absence of CD28 costimulation. J Immunol, 1996; 157(4):1752–1757

33.

Perrin

, Lavi

, Rumbley

, et al. Experimental autoimmune meningitis: a novel neurological disease in CD28-deficient mice. Clin Immunol, 1999; 91(1):41–49; doi: 10.1006/clim.1998.4684

34.

S-Y

, Mracsko

, Liesz

, et al. Amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice. Stroke, 2015; 46(1):212–220; doi: 10.1161/STROKEAHA.114.007756

35.

Gough

SCL

, Walker

LSK

, Sansom

. CTLA4 gene polymorphism and autoimmunity. Immunol Rev, 2005; 204(1):102–115; doi: 10.1111/j.0105-2896.2005.00249.x

36.

Schindler

, Pittaluga

, Enose-Akahata

, et al. Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder. J Clin Invest, 2020; 130(10):5551–5561; doi: 10.1172/JCI135947

37.

Wang

, Zhu

, Lu

, et al. CTLA-4 + 49 G/A polymorphism confers autoimmune disease risk: an updated meta-analysis. Genet Test Mol Biomarkers, 2017; 21(4):222–227; doi: 10.1089/gtmb.2016.0335

38.

Trynka

, Hunt

, Bockett

, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet, 2011; 43(12):1193–1201; doi: 10.1038/ng.998

39.

Okada

, Wu

, Trynka

, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 2014; 506(7488):376–381; doi: 10.1038/nature12873

40.

Shinoyama

, Ideguchi

, Hayashi

, et al. Cytotoxic T lymphocyte antigen 4 immunogloblin promotes neuronal differentiation in the grafts of embryonic stem cell-derived neural precursor cells. Neuroscience, 2012; 202:484–491; doi: 10.1016/j.neuroscience.2011.11.052

41.

Podojil

, Miller

. Targeting the B7 family of co-stimulatory molecules: successes and challenges. BioDrugs, 2013; 27(1):1–13; doi: 10.1007/s40259-012-0001-6

42.

Louveau

, Nerrière-Daguin

, Vanhove

, et al. Targeting the CD80/CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth. Glia, 2015; 63(12):2298–2312; doi: 10.1002/glia.22894

43.

, Oh

, Chu

, et al. Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts. Brain, 2019; 142(11):3456–3472; doi: 10.1093/brain/awz275

44.

Martin

, Plat

, Nerriére-Daguin

, et al. Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation. Transgenic Res, 2005; 14(4):373–384; doi: 10.1007/s11248-004-7268-4

45.

Uzan

, Tanriverdi

, Baykara

, et al. Association between interleukin-1 beta (IL-1β) gene polymorphism and outcome after head injury: an early report. Acta Neurochir (Wien), 2005; 147(7):715–720; doi: 10.1007/s00701-005-0529-z

46.

Waters

, Pober

, Bradley

. Tumour necrosis factor in infectious disease: TNF in infection. J Pathol, 2013; 230(2):132–147; doi: 10.1002/path.4187

47.

Chinen

, Kannan

, Levine

, et al. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol, 2016; 17(11):1322–1333; doi: 10.1038/ni.3540

48.

Rai

, Wakeland

. Genetic predisposition to autoimmunity – What have we learned?. Semin Immunol, 2011; 23(2):67–83; doi: 10.1016/j.smim.2011.01.015

49.

Huang

, Dauer

, Ha

, et al. Interleukin-2 deficiency-induced T cell autoimmunity in the mouse brain. Neurosci Lett, 2009; 463(1):44–48; doi: 10.1016/j.neulet.2009.07.013

50.

Yshii

, Pasciuto

, Bielefeld

, et al. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat Immunol, 2022; 23(6):878–891; doi: 10.1038/s41590-022-01208-z

51.

Liao

, Lin

J-X

, Leonard

. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity, 2013; 38(1):13–25; doi: 10.1016/j.immuni.2013.01.004

52.

Wylezinski

, Hawiger

. Interleukin 2 activates brain microvascular endothelial cells resulting in destabilization of adherens junctions. J Biol Chem, 2016; 291(44):22913–22923; doi: 10.1074/jbc.M116.729038

53.

Bodhankar

, Chen

, Vandenbark

, et al. IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metab Brain Dis, 2013; 28(3):375–386; doi: 10.1007/s11011-013-9413-3

54.

Liesz

, Bauer

, Hoheisel

, et al. Intracerebral interleukin-10 injection modulates post-ischemic neuroinflammation: an experimental microarray study. Neurosci Lett, 2014; 579:18–23; doi: 10.1016/j.neulet.2014.07.003

55.

Pousset

, Cremona

, Dantzer

, et al. Interleukin-4 and interleukin-10 regulate IL1-beta induced mouse primary astrocyte activation: a comparative study. Glia, 1999; 26(1):12–21; doi: 10.1002/(sici)1098-1136(199903)26:1<12::aid-glia2>3.0.co;2-s.

56.

Villacampa

, Almolda

, Vilella

, et al. Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy. Glia, 2015; 63(7):1166–1184; doi: 10.1002/glia.22807

57.

Chenouard

, Chesneau

, Braza

, et al. Phenotype and functions of B cells in patients with acute brain injuries. Mol Immunol, 2015; 68(2 Pt A):350–356; doi: 10.1016/j.molimm.2015.09.001

58.

Yasuda

, Takeuchi

, Hirota

. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol, 2019; 41(3):283–297; doi: 10.1007/s00281-019-00733-8

59.

Prescott

, Lehne

, Stone

, et al. Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genet, 2015; 11(2):e1004955; doi: 10.1371/journal.pgen.1004955

60.

Spolski

, Leonard

. IL-21 and T follicular helper cells. International Immunology, 2010; 22(1):7–12; doi: 10.1093/intimm/dxp112

61.

Bobbala

, Orkhis

, Kandhi

, et al. Interleukin-21-dependent modulation of T cell antigen receptor reactivity towards low affinity peptide ligands in autoreactive CD8(+) T lymphocytes. Cytokine, 2016; 85:83–91; doi: 10.1016/j.cyto.2016.06.011

62.

Ramanathan

, Dubois

, Chen

X-L

, et al. Exposure to IL-15 and IL-21 enables autoreactive CD8 T cells to respond to weak antigens and cause disease in a mouse model of autoimmune diabetes. J Immunol, 2011; 186(9):5131–5141; doi: 10.4049/jimmunol.1001221

63.

Niu

, He

, Zhang

, et al. IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol, 2010; 71(4):334–341; doi: 10.1016/j.humimm.2010.01.010

64.

Nurieva

, Yang

, Martinez

, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature, 2007; 448(7152):480–483; doi: 10.1038/nature05969

65.

Park

J-S

, Yoo

S-H

, Lim

M-A

, et al. A bispecific soluble receptor fusion protein that targets TNF-α and IL-21 for synergistic therapy in inflammatory arthritis. FASEB J, 2020; 34(1):248–262; doi: 10.1096/fj.201900816RR

66.

Tzartos

, Craner

, Friese

, et al. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol, 2011; 178(2):794–802; doi: 10.1016/j.ajpath.2010.10.043

67.

Higashioka

, Yoshimura

, Sakuragi

, et al. Human PD-1(hi)CD8(+) T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis. Front Immunol, 2021; 12:654623; doi: 10.3389/fimmu.2021.654623

68.

McGuire

, Vogelzang

, Ma

, et al. A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity. Immunity, 2011; 34(4):602–615; doi: 10.1016/j.immuni.2011.01.021

69.

Pontarini

, Murray-Brown

, Croia

, et al. Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma. Ann Rheum Dis, 2020; 79(12):1588–1599; doi: 10.1136/annrheumdis-2020-217646

70.

Jan

, Arafah

, Alsuwayni

, et al. Gene polymorphisms and their role in autoimmunity. In: A Molecular Approach to Immunogenetics. Elsevier: New York; 2022; pp. 143–168; doi: 10.1016/B978-0-323-90053-9.00009-9

71.

Nakayama

, Kosek

, Capone

, et al. Aiolos overexpression in systemic lupus erythematosus B cell subtypes and BAFF-induced memory B cell differentiation are reduced by CC-220 modulation of cereblon activity. J Immunol, 2017; 199(7):2388–2407; doi: 10.4049/jimmunol.1601725

72.

Garrett-Sinha

. Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci, 2013; 70(18):3375–3390; doi: 10.1007/s00018-012-1243-7

73.

, Ding

, Wang

, et al. Polymorphisms of IKZF3 gene and autoimmune thyroid diseases: associated with graves' disease but not with hashimoto's thyroiditis. Cell Physiol Biochem, 2018; 45(5):1787–1796; doi: 10.1159/000487870

74.

Keshari

, Harbo

, Myhr

K-M

, et al. Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood. BMC Genet, 2016; 17(1):59; doi: 10.1186/s12863-016-0367-4

75.

Eames

, Corbin

, Udalova

. Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease. Transl Res, 2016; 167(1):167–182; doi: 10.1016/j.trsl.2015.06.018

76.

Vandenbroeck

, Alloza

, Swaminathan

, et al. Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection. Genes Immun, 2011; 12(1):40–45; doi: 10.1038/gene.2010.46

77.

Armstrong

, Zidovetzki

, Alarcón-Riquelme

, et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun, 2014; 15(6):347–354; doi: 10.1038/gene.2014.23

78.

Tsao

H-W

, Tai

T-S

, Tseng

, et al. Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter. Proceedings of the National Academy of Sciences, 2013; 110(39):15776–15781; doi: 10.1073/pnas.1304343110

79.

Moisan

, Grenningloh

, Bettelli

, et al. Ets-1 is a negative regulator of Th17 differentiation. J Exp Med, 2007; 204(12):2825–2835; doi: 10.1084/jem.20070994

80.

Kim

, Lee

C-G

, Jung

J-Y

, et al. The transcription factor Ets1 suppresses T Follicular Helper Type 2 cell differentiation to halt the onset of systemic lupus erythematosus. Immunity, 2018; 49(6):1034-1048.e8; doi: 10.1016/j.immuni.2018.10.012

81.

Cortés

, Georgopoulos

. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med, 2004; 199(2):209–219; doi: 10.1084/jem.20031571

82.

Mazzurana

, Forkel

, Rao

, et al. Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation. Eur J Immunol, 2019; 49(9):1344–1355; doi: 10.1002/eji.201848075

83.

Monticelli

, Sallusto

. Negative regulators take center stage. Nat Immunol, 2012; 13(8):719–720; doi: 10.1038/ni.2377.

84.

Yang

, Zhang

, Jing

, et al. IRF5 Acts as a Potential Therapeutic Marker in Inflammatory Bowel Diseases. Inflamm Bowel Dis, 2021; 27(3):407–417; doi: 10.1093/ibd/izaa200

85.

Dideberg

, Kristjansdottir

, Milani

, et al. An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet, 2007; 16(24):3008–3016; doi: 10.1093/hmg/ddm259

86.

Witcher

, Bray

, Chunchai

, et al. Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by microglia. J Neurosci, 2021; 41(7):1597–1616; doi: 10.1523/JNEUROSCI.2469-20.2020

87.

Wangler

, Bray

, Packer

, et al. Amplified gliosis and interferon-associated inflammation in the aging brain following diffuse traumatic brain injury. J Neurosci, 2022; 42(48):9082–9096; doi: 10.1523/JNEUROSCI.1377-22.2022

88.

Barrett

, Knoblach

, Bhattacharya

, et al. Traumatic brain injury induces cGAS activation and type I Interferon signaling in aged mice. Front Immunol, 2021; 12:710608; doi: 10.3389/fimmu.2021.710608

89.

Barrett

, Henry

, Shirey

, et al. Interferon-β plays a detrimental role in experimental traumatic brain injury by enhancing neuroinflammation that drives chronic neurodegeneration. J Neurosci, 2020; 40(11):2357–2370; doi: 10.1523/JNEUROSCI.2516-19.2020

90.

Roychoudhuri

, Hirahara

, Mousavi

, et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature, 2013; 498(7455):506–510; doi: 10.1038/nature12199

91.

Sheng

, Zhang

, Li

, et al. Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in systemic lupus erythematosus. FEBS Open Bio, 2020; 11(2):395–403; doi: 10.1002/2211-5463.13050

92.

Zhang

, Hu

, Zhang

, et al. Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity. Front Immunol, 2019; 10:2050; doi: 10.3389/fimmu.2019.02050.

93.

Lee

, Boone

, Chai

, et al. Failure to regulate TNF-induced NF-κB and Cell death responses in A20-deficient mice. Science, 2000; 289(5488):2350–2354; doi: 10.1126/science.289.5488.2350

94.

Wertz

, O'Rourke

, Zhou

, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature, 2004; 430(7000):694–699; doi: 10.1038/nature02794

95.

Tavares

, Turer

, Liu

, et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity, 2010; 33(2):181–191; doi: 10.1016/j.immuni.2010.07.017

96.

Musone

, Taylor

, Lu

, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet, 2008; 40(9):1062–1064; doi: 10.1038/ng.202

97.

Hah

Y-S

, Lee

Y-R

, Jun

J-S

, et al. A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis. Arthritis & Rheumatism, 2010; 62(8):2313–2321; doi: 10.1002/art.27545

98.

Gilli

, Navone

, Perga

, et al. Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis. Arch Neurol, 2011; 68(7):879–888; doi: 10.1001/archneurol.2011.32

99.

Onizawa

, Oshima

, Schulze-Topphoff

, et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol, 2015; 16(6):618–627; doi: 10.1038/ni.3172

100.

Bao

, Fan

, Zhao

, et al. Silencing of A20 aggravates neuronal death and inflammation after traumatic brain injury: a potential trigger of necroptosis. Front Mol Neurosci, 2019; 12:222; doi: 10.3389/fnmol.2019.00222

101.

Song

, Zhuang

, Zhu

, et al. Differential roles of human PUS10 in miRNA processing and tRNA pseudouridylation. Nat Chem Biol, 2020; 16(2):160–169; doi: 10.1038/s41589-019-0420-5

102.

Aza-Blanc

, Cooper

, Wagner

, et al. Identification of Modulators of TRAIL-Induced Apoptosis via RNAi-Based Phenotypic Screening. Mol Cell, 2003; 12(3):627–637; doi: 10.1016/S1097-2765(03)00348-4

103.

, Ding

, Qin

, et al. Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci. J Cancer, 2020; 11(5):1075–1081; doi: 10.7150/jca.35127

104.

Hering

, Katkeviciute

, Schwarzfischer

, et al. Protein tyrosine phosphatase non-receptor type 2 function in dendritic cells is crucial to maintain tissue tolerance. Front Immunol, 2020; 11:1856; doi: 10.3389/fimmu.2020.01856

105.

Chung

, Criswell

. PTPN22: its role in SLE and autoimmunity. Autoimmunity, 2007; 40(8):582–590; doi: 10.1080/08916930701510848

106.

Yang

S-K

, Hong

, Choi

, et al. Immunochip analysis identification of 6 additional susceptibility loci for Crohn's disease in Koreans. Inflamm Bowel Dis, 2015; 21(1):1–7; doi: 10.1097/MIB.0000000000000268

107.

Onengut-Gumuscu

, Chen

W-M

, Burren

, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet, 2015; 47(4):381–386; doi: 10.1038/ng.3245

108.

Scharl

, Mwinyi

, Fischbeck

, et al. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis, 2012; 18(5):900–912; doi: 10.1002/ibd.21913

109.

Wiede

, Shields

, Chew

, et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest, 2011; 121(12):4758–4774; doi: 10.1172/JCI59492

110.

Wiede

, Sacirbegovic

, Leong

, et al. PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity. J Autoimmun, 2017; 76:85–100; doi: 10.1016/j.jaut.2016.09.004

111.

Mustelin

, Bottini

, Stanford

. The Ccntribution of PTPN22 to rheumatic disease. Arthritis Rheumatol, 2019; 71(4):486–495; doi: 10.1002/art.40790

112.

Zheng

, Ibrahim

, Petersen

, et al. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue. Genes Immun, 2012; 13(8):641–652; doi: 10.1038/gene.2012.46

113.

Seldin

, Shigeta

, Laiho

, et al. Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis. Genes Immun, 2005; 6(8):720–722; doi: 10.1038/sj.gene.6364255

114.

Perri

, Pellegrino

, Ceccacci

, et al. Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes. PLoS One, 2017; 12(4):e0175784; doi: 10.1371/journal.pone.0175784

115.

Pellegrino

, Ceccacci

, Petrini

, et al. Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes. Nanomedicine, 2019; 18:371–379; doi: 10.1016/j.nano.2018.11.001

116.

Perez-Garcia

, Ambesi-Impiombato

, Hadler

, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood, 2013; 122(14):2425–2432; doi: 10.1182/blood-2013-05-500850

117.

Mori

, Iwasaki

, Seki

, et al. Lnk/Sh2b3 controls the production and function of dendritic cells and regulates the induction of IFN-γ-producing T cells. J Immunol, 2014; 193(4):1728–1736; doi: 10.4049/jimmunol.1303243

118.

Katayama

, Mori

, Seki

, et al. Lnk prevents inflammatory CD8⁺ T-cell proliferation and contributes to intestinal homeostasis. Eur J Immunol, 2014; 44(6):1622–1632; doi: 10.1002/eji.201343883

119.

Allenspach

, Shubin

, Cerosaletti

, et al. The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis. J Immunol, 2021; 207(11):2710–2719; doi: 10.4049/jimmunol.2100454

120.

Chen

, He

, Sun

, et al. TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response. Nat Commun, 2020; 11(1):1913; doi: 10.1038/s41467-020-15564-7

121.

Land

, Moll

, Kaplan

, et al. Signal Transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in graves' hyperthyroidism. Endocrinology, 2004; 145(8):3724–3730; doi: 10.1210/en.2004-0352

122.

Usui

, Nishikomori

, Kitani

, et al. GATA-3 suppresses Th1 development by downregulation of Stat4 and not through Efeects on IL-12Rβ2 chain or T-bet. Immunity, 2003; 18(3):415–428; doi: 10.1016/S1074-7613(03)00057-8

123.

, Yang

, Qiu

, et al. Stat4 Is critical for the balance between Th17 cells and regulatory T cells in colitis. J Immunol, 2011; 186(11):6597–6606; doi: 10.4049/jimmunol.1004074

124.

Oliver-Martos

, Órpez

, Pinto-Medel

, et al. Gene expression in IFNß signalling pathway differs between monocytes, CD4 and CD8 T cells from MS patients. J Neuroimmunol, 2011; 230(1–2):153–159; doi: 10.1016/j.jneuroim.2010.10.033

125.

Sohn

, Barrett

, Van Abbema

, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol, 2013; 191(5):2205–2216; doi: 10.4049/jimmunol.1202859