The new quest in CTLA-4 insufficiency: How to immune modulate effectively?

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity (IEIs) wherein immune dysregulation is a prominent feature. Immune dysregulation may manifest as any combination of autoimmunity, lymphoproliferation, early-onset malignancy, and/or severe atopy. PIRDs require a more targeted approach to therapy than do antibody deficiency syndromes, which can usually be easily managed with immune globulin replacement and antimicrobial prophylaxis. Immune modulation using precision therapies such as sirolimus and cytotoxic T-lymphocyte antigen-4 (CTLA-4)-immunoglobulin (ie, abatacept and belatacept) may improve outcomes, but these therapies necessitate close follow-up, and many questions remain regarding the best treatment modality, dosing, duration of therapy, and how to monitor treatment response. If a PIRD is not recognized until adulthood, chronic immune dysregulation may escalate to hard-to-reverse end-organ damage (ie, granulomatous lung disease, gastrointestinal involvement, massive splenomegaly, etc). In some cases, immune dysregulation is so severe that patients undergo hematopoietic stem cell transplantation (HSCT). Optimal management of PIRDs involves collaboration between immunology, pulmonology, rheumatology, hematology/oncology, gastroenterology, neurology, and even transplant services to manage autoimmune, lymphoproliferative, and malignant complications. In summary, PIRDs are often high in complexity, and they may affect several organ systems, which requires a multispecialty approach. The article by Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar in this issue of the Journal of Allergy and Clinical Immunology highlights the complexity of diagnosis and treatment regimens in patients with CTLA-4 insufficiency, a prototypical and common form of PIRD.Briefly, CTLA-4 insufficiency was initially described in 2014, as a form of immune dysregulation inherited in an autosomal dominant manner with incomplete penetrance.2Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (582) Google Scholar Patients with CTLA-4 insufficiency were historically labeled as having common variable immune deficiency, but genetic testing permits a more specific diagnosis and points to targeted therapy with CTLA-4–immunoglobulin. However, the molecular biology and immunobiology of CTLA-4 insufficiency and best treatment modalities are still not fully understood.In healthy individuals, CTLA-4 is expressed constitutively on regulatory T (Treg) cells and on other T cells following activation. It plays a crucial role in the immunologic synapse, where a T cell and antigen-presenting cell (APC) interact. A naive T cell requires 2 signals for activation; the first occurs when APCs present antigen via MHC and engage a T-cell receptor. To avoid apoptosis or anergy of the T cells, a costimulatory “second signal” is required and occurs when CD28 on T cells binds CD80 or CD86 on APCs (Fig 1). In normal circumstances, CTLA-4 binds CD80/CD86 on the APC with higher affinity than does CD28, thereby modulating T-cell activation. Furthermore, CTLA-4 extracts its CD80/CD86 ligand from the surface of the APC. This mechanism is termed transendocytosis.3Qureshi O.S. Zheng Y. Nakamura K. Attridge K. Manzotti C. Schmidt E.M. et al.Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.Science. 2011; 332: 600-603Crossref PubMed Scopus (1035) Google Scholar In CTLA-4 insufficiency, reduced surface expression and/or dysfunctional protein expression results in unchecked T-cell activation. Unchecked T-cell activation is undesirable because it can promote survival of autoreactive T cells, resulting in autoimmunity and lymphoproliferation. An increasing body of evidence shows that CTLA-4 acts in a cell-extrinsic manner (ie, via transendocytosis), which is to say that CTLA-4 affects the cells in its vicinity rather than the cell expressing it.4Hou T.Z. Qureshi O.S. Wang C.J. Baker J. Young S.P. Walker L.S. et al.A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.J Immunol. 2015; 194: 2148-2159Crossref PubMed Scopus (67) Google ScholarCTLA-4 variants and/or CTLA-4 deficiency creates challenges for clinicians in 2 respects. First, CTLA-4 insufficiency displays variable clinical phenotype even in patients with the same genetic variant; therefore, clinicians may be unable to predict the disease course of individual patients (incomplete penetrance). In fact, patients who carry CTLA4 pathogenic variants often remain asymptomatic until adolescence or young adulthood, and family members who bear identical pathogenic variants may show widely disparate clinical features. End-organ damage may occur with age and require input from a variety of specialists. Patients may present first to hematology for autoimmune cytopenia, to gastroenterology for inflammatory bowel or liver disease, to rheumatology for arthritis or vasculitis, or to neurology with neuropsychiatric symptoms. Incomplete penetrance also implies that factors beyond the genetic code, be they epigenetic or environmental triggers, also affect the clinical phenotype of CLTA-4 insufficiency.Second, for specific CTLA4 variants, functional data may not be available, which lowers confidence in the potential pathogenicity of novel variants. Phenotype at the protein level is challenging to discern. The fact that CTLA-4 forms homodimers complicates questions of haploinsufficiency versus dominant negative effects of nonfunctional alleles. Some CTLA4 mutations fully abrogate protein expression (“haploinsufficiency”), and the 50% loss of “gene dosage” of CTLA4 appears to be salient to phenotype in haploinsufficient individuals.4Hou T.Z. Qureshi O.S. Wang C.J. Baker J. Young S.P. Walker L.S. et al.A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.J Immunol. 2015; 194: 2148-2159Crossref PubMed Scopus (67) Google Scholar,5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google ScholarOther point mutations in the ligand binding domain of CTLA-4 permit full-length protein expression, but the mutant protein exerts a “dominant negative effect” on the “normal” protein. In some cases, CTLA-4 cannot bind CD80/CD86 secondary to diminished ligand affinity or structural abnormalities of CTLA-4 homodimers.5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google Scholar In addition, dynamic recycling and trafficking of CTLA-4 between cytosol and membrane may affect phenotype in ways not yet understood. In an effort to gain traction on explaining phenotypic variance, the impact of CTLA4 point mutations has been studied in vitro5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google Scholar and in silico.6Khailaie S. Rowshanravan B. Robert P.A. Waters E. Halliday N. Badillo Herrera J.D. et al.Characterization of CTLA4 Trafficking and Implications for Its Function.Biophys J. 2018; 115: 1330-1343Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Finally, improved understanding of the mechanobiology of the immunologic synapse may help provide clarity regarding CTLA-4 function and possible additional therapies.In Egg et al,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar CTLA-4 insufficiency is assessed first by genetic testing. Novel variants of uncertain significance require functional assays for confirmation, namely the transendocytosis assay and/or surface staining for CTLA-4 expression on Treg cells1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (assays that are available only at certain academic centers). The current cohort of 173 patients represents 53 distinct CTLA4 variants and includes 4 novel variants with confirmed pathogenicity. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar note that the transendocytosis assay is preferred over surface staining for CTLA-4 expression, which was less sensitive for diagnosing CTLA-4 insufficiency. Given the aforementioned challenges in parsing haploinsufficiency versus dominant negative effects, the transendocytosis assay provides a better understanding of how a specific genetic defect affects protein function.The goals of treatment in CTLA-4 insufficiency include alleviating autoimmune and lymphoproliferative complications, as well as infection prevention. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar enumerate treatment approaches used in this large cohort systematically, by organ system, and provide valuable insight into which therapies have been empirically trialed in patients with CTLA-4 insufficiency. Although a plethora of immune modulators have been trialed, a consensus has not yet emerged about the best course of therapy for each organ-specific complication in CTLA-4 insufficiency. Patients with multisystem involvement are uniquely challenging, because the most effective immune modulator for pulmonary complications may not be the best choice for gut involvement. As the median age of diagnosis was 26 years, it is likely that some patients received conventional therapy for noninfectious complications, such as corticosteroids, before CTLA-4 insufficiency was diagnosed. Overall, the numbers of patients treated with each therapy are quite small, although the current study is the largest CTLA-4 insufficiency cohort to date.On the whole, Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar suggest that symptomatic lymphocytic infiltration (gut, lung, and brain) should initially be treated with corticosteroids, rituximab, or both, but they provide more nuanced suggestions in sections dedicated to each organ system. Although a T-cell infiltrative process is often seen on pathology specimens, the authors note that B-cell–directed rituximab is “clinically very efficient,” for treating lymphoid infiltrations, as rituximab depletes B cells expressing CD80/86, thus removing one of the triggers for T-cell activation. Of course, rituximab does not directly deplete other APCs such as dendritic cells. We find that rituximab is most effective for granulomatous-lymphocytic interstitial lung disease, often in combination with T-cell modulators, whereas T-cell–directed therapies are more effective for gut and brain involvement.In their Discussion section, Egg et al share detailed recommendations for management of each involved organ system. Abatacept is recommended as a first-line steroid-sparing agent for granulomatous-lymphocytic interstitial lung disease, enteropathy, and neurologic involvement. Sirolimus and other T-cell modulators may also be considered. Abatacept seems to be very promising for treatment of a variety of complications of CTLA-4 insufficiency, and a forthcoming article by the Egg et al (on the results of the ABACHAI trial) will examine the long-term safety of abatacept in CTLA-4 insufficiency. Dosing recommendations for specific noninfectious complications are not yet clear. In future studies, segregating treatment approach among those with early versus late diagnosis of CTLA-4 insufficiency would be useful. Optimal dosing of abatacept is not yet defined; different dosing regimens are currently in trials, and the best available evidence on dosing comes from LPS-responsive beige-like anchor protein (LRBA) deficiency.7Kiykim A. Ogulur I. Dursun E. Charbonnier L.M. Nain E. Cekic S. et al.Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency.J Allergy Clin Immunol Pract. 2019; 7: 2790-2800.e15Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Splenectomy should be avoided in CTLA-4 insufficiency, as the clinical response is not sustained,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar and infection risk is higher after splenectomy. In addition, patients with CTLA-4 insufficiency are at risk of malignancy, in particular, EBV-driven gastric carcinoma and lymphoma. Blood levels of EBV and cytomegalovirus viral load should be monitored during abatacept therapy, as patients can develop viremia, lymphoproliferation, and ultimately neoplasms.8Schwab C. Gabrysch A. Olbrich P. Patino V. Warnatz K. Wolff D. et al.Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.J Allergy Clin Immunol. 2018; 142: 1932-1946Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar A better understanding of CTLA-4 molecular biology would facilitate research on new tailored therapies. Edner et al9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google Scholar review the various forms of CTLA-4–immunoglobulin now available (abatacept and belatacept), as well as others in development, which vary primarily in their binding affinities for CD80 and CD86. Edner et al9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google Scholar also discuss other potential therapies that could someday be meaningful in CTLA-4 insufficiency, including antagonistic anti-CD28 antibodies, low-dose agonistic anti-CD28 antibodies that preferentially target Treg cells (skirting the risk of cytokine storm), and antibodies to inducible costimulator/inducible costimulator ligand.9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google ScholarResearch to identify biomarkers treatment response is ongoing. T follicular helper cells, CD19hiCD21lo B cells, and soluble IL-2 may be helpful as disease markers when tracking response to therapy, as has been noted in LRBA deficiency (Table I).10Alroqi F.J. Charbonnier L.M. Baris S. Kiykim A. Chou J. Platt C.D. et al.Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation.J Allergy Clin Immunol. 2018; 141: 1050-1059.e10Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar However, such biomarkers are not readily available clinically.Table ISummary of CTLA-4 insufficiency presentation, diagnosis, and treatmentClinical presentation•Immune dysregulation: autoimmunity, lymphoproliferation, malignancy, and/or atopy•Infection, hypogammaglobulinemia•Often presents in adolescence or young adulthoodDiagnosis•Genetic testing (ie, primary immunodeficiency panel)•Confirmatory functional testing (transendocytosis assay and/or surface stain for CTLA-4 expression)Treatment options•Immune globulin•Corticosteroids•Rituximab•Immune modulators: abatacept, sirolimus, mycophenolate mofetil, etc, depending on end-organ involvement•HSCTCandidate biomarkers for severity of immune dysregulation•Unique cell subsets such as T follicular helper cells, double-negative T cells, CD19hi21CDlo B cells•Serum biomarkers: soluble IL-2 receptor Open table in a new tab As genetic testing expands, asymptomatic family members are being diagnosed with CTLA-4 insufficiency, and these carriers provide unique insight into the evolution of disease and the potential for prevention. It is tempting to think that we might prevent future complications by giving these patients what they lack on the molecular level, which is exactly the promise of CTLA-4–immunoglobulin. As noted by Egg et al,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar whether abatacept works prophylactically to prevent progression of disease is not yet known. Other unknowns include adverse effects of long-term abatacept use and effect on median survival. Similarly, should HSCT be considered in young, oligosymptomatic patients or those with early immune dysregulation? HSCT is safer and more effective in young patients than in older patients, and the historically low median survival of patients with CTLA-4 insufficiency makes the idea of “prophylactic HSCT” appealing. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar state that “red flags” for considering early HSCT include treatment-refractory cytopenia (the most common reason for HSCT in this study), central nervous system disease, enteropathy, and lung involvement. There is a need for guidance on criteria, timing of HSCT, and best conditioning approach.Prospective clinical trials are needed; examples include the ABACHAI trial forthcoming from Egg et al and the 6906 protocol by the Primary Immune Deficiency Treatment Consortium (looking at HSCT, biologics, and small molecule therapies), to improve understanding of molecular events, natural history, and treatment response. Questions remain regarding optimal choice of therapy, dosing, monitoring treatment response, and prophylactic treatment of asymptomatic or oligosymptomatic patients. A better understanding of the molecular biology of CTLA-4 may also support the use of functional assays and specific biomarkers to inform therapy. Primary immune regulatory disorders (PIRDs) are inborn errors of immunity (IEIs) wherein immune dysregulation is a prominent feature. Immune dysregulation may manifest as any combination of autoimmunity, lymphoproliferation, early-onset malignancy, and/or severe atopy. PIRDs require a more targeted approach to therapy than do antibody deficiency syndromes, which can usually be easily managed with immune globulin replacement and antimicrobial prophylaxis. Immune modulation using precision therapies such as sirolimus and cytotoxic T-lymphocyte antigen-4 (CTLA-4)-immunoglobulin (ie, abatacept and belatacept) may improve outcomes, but these therapies necessitate close follow-up, and many questions remain regarding the best treatment modality, dosing, duration of therapy, and how to monitor treatment response. If a PIRD is not recognized until adulthood, chronic immune dysregulation may escalate to hard-to-reverse end-organ damage (ie, granulomatous lung disease, gastrointestinal involvement, massive splenomegaly, etc). In some cases, immune dysregulation is so severe that patients undergo hematopoietic stem cell transplantation (HSCT). Optimal management of PIRDs involves collaboration between immunology, pulmonology, rheumatology, hematology/oncology, gastroenterology, neurology, and even transplant services to manage autoimmune, lymphoproliferative, and malignant complications. In summary, PIRDs are often high in complexity, and they may affect several organ systems, which requires a multispecialty approach. The article by Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar in this issue of the Journal of Allergy and Clinical Immunology highlights the complexity of diagnosis and treatment regimens in patients with CTLA-4 insufficiency, a prototypical and common form of PIRD. Briefly, CTLA-4 insufficiency was initially described in 2014, as a form of immune dysregulation inherited in an autosomal dominant manner with incomplete penetrance.2Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (582) Google Scholar Patients with CTLA-4 insufficiency were historically labeled as having common variable immune deficiency, but genetic testing permits a more specific diagnosis and points to targeted therapy with CTLA-4–immunoglobulin. However, the molecular biology and immunobiology of CTLA-4 insufficiency and best treatment modalities are still not fully understood. In healthy individuals, CTLA-4 is expressed constitutively on regulatory T (Treg) cells and on other T cells following activation. It plays a crucial role in the immunologic synapse, where a T cell and antigen-presenting cell (APC) interact. A naive T cell requires 2 signals for activation; the first occurs when APCs present antigen via MHC and engage a T-cell receptor. To avoid apoptosis or anergy of the T cells, a costimulatory “second signal” is required and occurs when CD28 on T cells binds CD80 or CD86 on APCs (Fig 1). In normal circumstances, CTLA-4 binds CD80/CD86 on the APC with higher affinity than does CD28, thereby modulating T-cell activation. Furthermore, CTLA-4 extracts its CD80/CD86 ligand from the surface of the APC. This mechanism is termed transendocytosis.3Qureshi O.S. Zheng Y. Nakamura K. Attridge K. Manzotti C. Schmidt E.M. et al.Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.Science. 2011; 332: 600-603Crossref PubMed Scopus (1035) Google Scholar In CTLA-4 insufficiency, reduced surface expression and/or dysfunctional protein expression results in unchecked T-cell activation. Unchecked T-cell activation is undesirable because it can promote survival of autoreactive T cells, resulting in autoimmunity and lymphoproliferation. An increasing body of evidence shows that CTLA-4 acts in a cell-extrinsic manner (ie, via transendocytosis), which is to say that CTLA-4 affects the cells in its vicinity rather than the cell expressing it.4Hou T.Z. Qureshi O.S. Wang C.J. Baker J. Young S.P. Walker L.S. et al.A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.J Immunol. 2015; 194: 2148-2159Crossref PubMed Scopus (67) Google Scholar CTLA-4 variants and/or CTLA-4 deficiency creates challenges for clinicians in 2 respects. First, CTLA-4 insufficiency displays variable clinical phenotype even in patients with the same genetic variant; therefore, clinicians may be unable to predict the disease course of individual patients (incomplete penetrance). In fact, patients who carry CTLA4 pathogenic variants often remain asymptomatic until adolescence or young adulthood, and family members who bear identical pathogenic variants may show widely disparate clinical features. End-organ damage may occur with age and require input from a variety of specialists. Patients may present first to hematology for autoimmune cytopenia, to gastroenterology for inflammatory bowel or liver disease, to rheumatology for arthritis or vasculitis, or to neurology with neuropsychiatric symptoms. Incomplete penetrance also implies that factors beyond the genetic code, be they epigenetic or environmental triggers, also affect the clinical phenotype of CLTA-4 insufficiency. Second, for specific CTLA4 variants, functional data may not be available, which lowers confidence in the potential pathogenicity of novel variants. Phenotype at the protein level is challenging to discern. The fact that CTLA-4 forms homodimers complicates questions of haploinsufficiency versus dominant negative effects of nonfunctional alleles. Some CTLA4 mutations fully abrogate protein expression (“haploinsufficiency”), and the 50% loss of “gene dosage” of CTLA4 appears to be salient to phenotype in haploinsufficient individuals.4Hou T.Z. Qureshi O.S. Wang C.J. Baker J. Young S.P. Walker L.S. et al.A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.J Immunol. 2015; 194: 2148-2159Crossref PubMed Scopus (67) Google Scholar,5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google Scholar Other point mutations in the ligand binding domain of CTLA-4 permit full-length protein expression, but the mutant protein exerts a “dominant negative effect” on the “normal” protein. In some cases, CTLA-4 cannot bind CD80/CD86 secondary to diminished ligand affinity or structural abnormalities of CTLA-4 homodimers.5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google Scholar In addition, dynamic recycling and trafficking of CTLA-4 between cytosol and membrane may affect phenotype in ways not yet understood. In an effort to gain traction on explaining phenotypic variance, the impact of CTLA4 point mutations has been studied in vitro5Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (563) Google Scholar and in silico.6Khailaie S. Rowshanravan B. Robert P.A. Waters E. Halliday N. Badillo Herrera J.D. et al.Characterization of CTLA4 Trafficking and Implications for Its Function.Biophys J. 2018; 115: 1330-1343Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Finally, improved understanding of the mechanobiology of the immunologic synapse may help provide clarity regarding CTLA-4 function and possible additional therapies. In Egg et al,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar CTLA-4 insufficiency is assessed first by genetic testing. Novel variants of uncertain significance require functional assays for confirmation, namely the transendocytosis assay and/or surface staining for CTLA-4 expression on Treg cells1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (assays that are available only at certain academic centers). The current cohort of 173 patients represents 53 distinct CTLA4 variants and includes 4 novel variants with confirmed pathogenicity. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar note that the transendocytosis assay is preferred over surface staining for CTLA-4 expression, which was less sensitive for diagnosing CTLA-4 insufficiency. Given the aforementioned challenges in parsing haploinsufficiency versus dominant negative effects, the transendocytosis assay provides a better understanding of how a specific genetic defect affects protein function. The goals of treatment in CTLA-4 insufficiency include alleviating autoimmune and lymphoproliferative complications, as well as infection prevention. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar enumerate treatment approaches used in this large cohort systematically, by organ system, and provide valuable insight into which therapies have been empirically trialed in patients with CTLA-4 insufficiency. Although a plethora of immune modulators have been trialed, a consensus has not yet emerged about the best course of therapy for each organ-specific complication in CTLA-4 insufficiency. Patients with multisystem involvement are uniquely challenging, because the most effective immune modulator for pulmonary complications may not be the best choice for gut involvement. As the median age of diagnosis was 26 years, it is likely that some patients received conventional therapy for noninfectious complications, such as corticosteroids, before CTLA-4 insufficiency was diagnosed. Overall, the numbers of patients treated with each therapy are quite small, although the current study is the largest CTLA-4 insufficiency cohort to date. On the whole, Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar suggest that symptomatic lymphocytic infiltration (gut, lung, and brain) should initially be treated with corticosteroids, rituximab, or both, but they provide more nuanced suggestions in sections dedicated to each organ system. Although a T-cell infiltrative process is often seen on pathology specimens, the authors note that B-cell–directed rituximab is “clinically very efficient,” for treating lymphoid infiltrations, as rituximab depletes B cells expressing CD80/86, thus removing one of the triggers for T-cell activation. Of course, rituximab does not directly deplete other APCs such as dendritic cells. We find that rituximab is most effective for granulomatous-lymphocytic interstitial lung disease, often in combination with T-cell modulators, whereas T-cell–directed therapies are more effective for gut and brain involvement. In their Discussion section, Egg et al share detailed recommendations for management of each involved organ system. Abatacept is recommended as a first-line steroid-sparing agent for granulomatous-lymphocytic interstitial lung disease, enteropathy, and neurologic involvement. Sirolimus and other T-cell modulators may also be considered. Abatacept seems to be very promising for treatment of a variety of complications of CTLA-4 insufficiency, and a forthcoming article by the Egg et al (on the results of the ABACHAI trial) will examine the long-term safety of abatacept in CTLA-4 insufficiency. Dosing recommendations for specific noninfectious complications are not yet clear. In future studies, segregating treatment approach among those with early versus late diagnosis of CTLA-4 insufficiency would be useful. Optimal dosing of abatacept is not yet defined; different dosing regimens are currently in trials, and the best available evidence on dosing comes from LPS-responsive beige-like anchor protein (LRBA) deficiency.7Kiykim A. Ogulur I. Dursun E. Charbonnier L.M. Nain E. Cekic S. et al.Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency.J Allergy Clin Immunol Pract. 2019; 7: 2790-2800.e15Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Splenectomy should be avoided in CTLA-4 insufficiency, as the clinical response is not sustained,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar and infection risk is higher after splenectomy. In addition, patients with CTLA-4 insufficiency are at risk of malignancy, in particular, EBV-driven gastric carcinoma and lymphoma. Blood levels of EBV and cytomegalovirus viral load should be monitored during abatacept therapy, as patients can develop viremia, lymphoproliferation, and ultimately neoplasms.8Schwab C. Gabrysch A. Olbrich P. Patino V. Warnatz K. Wolff D. et al.Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.J Allergy Clin Immunol. 2018; 142: 1932-1946Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar A better understanding of CTLA-4 molecular biology would facilitate research on new tailored therapies. Edner et al9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google Scholar review the various forms of CTLA-4–immunoglobulin now available (abatacept and belatacept), as well as others in development, which vary primarily in their binding affinities for CD80 and CD86. Edner et al9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google Scholar also discuss other potential therapies that could someday be meaningful in CTLA-4 insufficiency, including antagonistic anti-CD28 antibodies, low-dose agonistic anti-CD28 antibodies that preferentially target Treg cells (skirting the risk of cytokine storm), and antibodies to inducible costimulator/inducible costimulator ligand.9Edner N.M. Carlesso G. Rush J.S. Walker L.S.K. Targeting co-stimulatory molecules in autoimmune disease.Nat Rev Drug Discov. 2020; 19: 860-883Crossref PubMed Scopus (46) Google Scholar Research to identify biomarkers treatment response is ongoing. T follicular helper cells, CD19hiCD21lo B cells, and soluble IL-2 may be helpful as disease markers when tracking response to therapy, as has been noted in LRBA deficiency (Table I).10Alroqi F.J. Charbonnier L.M. Baris S. Kiykim A. Chou J. Platt C.D. et al.Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation.J Allergy Clin Immunol. 2018; 141: 1050-1059.e10Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar However, such biomarkers are not readily available clinically. As genetic testing expands, asymptomatic family members are being diagnosed with CTLA-4 insufficiency, and these carriers provide unique insight into the evolution of disease and the potential for prevention. It is tempting to think that we might prevent future complications by giving these patients what they lack on the molecular level, which is exactly the promise of CTLA-4–immunoglobulin. As noted by Egg et al,1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar whether abatacept works prophylactically to prevent progression of disease is not yet known. Other unknowns include adverse effects of long-term abatacept use and effect on median survival. Similarly, should HSCT be considered in young, oligosymptomatic patients or those with early immune dysregulation? HSCT is safer and more effective in young patients than in older patients, and the historically low median survival of patients with CTLA-4 insufficiency makes the idea of “prophylactic HSCT” appealing. Egg et al1Egg D. Rump I.C. Mitsuiki N. Rojas-Restrepo J. Maccari M.E. Schwab C. et al.Therapeutic options for CTLA-4 insufficiency.J Allergy Clin Immunol. 2022; 149: 736-746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar state that “red flags” for considering early HSCT include treatment-refractory cytopenia (the most common reason for HSCT in this study), central nervous system disease, enteropathy, and lung involvement. There is a need for guidance on criteria, timing of HSCT, and best conditioning approach. Prospective clinical trials are needed; examples include the ABACHAI trial forthcoming from Egg et al and the 6906 protocol by the Primary Immune Deficiency Treatment Consortium (looking at HSCT, biologics, and small molecule therapies), to improve understanding of molecular events, natural history, and treatment response. Questions remain regarding optimal choice of therapy, dosing, monitoring treatment response, and prophylactic treatment of asymptomatic or oligosymptomatic patients. A better understanding of the molecular biology of CTLA-4 may also support the use of functional assays and specific biomarkers to inform therapy. Therapeutic options for CTLA-4 insufficiencyJournal of Allergy and Clinical ImmunologyVol. 149Issue 2PreviewHeterozygous germline mutations in cytotoxic T lymphocyte–associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. Full-Text PDF