Daniella M Schwartz, MD (she/her/hers), University of Pittsburgh Medical Center, Pittsburgh, USA
2023 has been marked by the discovery of over 10 new inborn errors of immunity, as well as novel consequences of anticytokine antibodies and somatic disease-causing variants. Amongst these were three new diseases caused by mutations in the JAK-STAT pathway. Baris et al and Sharma et al independently described a novel atopic syndrome caused by heterozygous germline gain-of-function (GOF) mutations in STAT6 1,2. This included 11 separate families across multiple continents and included atopic dermatitis, peripheral hypereosinophilia, eosinophilic gastrointestinal disease, allergic asthma, elevated total serum IgE, food allergy, and anaphylaxis. Mutations were found in the DNA-binding, linker, and SH2 domains: functional evaluation revealed sustained STAT6 phosphorylation and enhanced Th2 differentiation. Three families with disabling pansclerotic morphea due to heterozygous STAT4 GOF were described by Bhagdassarian et al 3. All three activating mutations were in the SH2 domain of STAT4; the mutant protein exhibited enhanced basal (unstimulated) phosphorylation and delayed dephosphorylation kinetics in skin fibroblasts. Patient skin and serum was characterized by markedly increased expression of IL-6. Further supporting a primary role for JAK-STAT pathway activation, both STAT6 GOF and STAT4 GOF patients responded to treatment with systemic JAK inhibitions like ruxolitinib and baricitinib.
Another major cytokine implicated in inborn errors of immunity is IL-1b, which is cleaved and activated downstream of various inflammasome complexes. A missense variant in the IL-1 receptor 1 (IL1R1) was found by Wang et al to cause a novel autoinflammatory disorder comprising recurrent sterile osteomyelitis 4. The pathogenic variant, K131E, disrupted the binding of the receptor antagonist ligand IL-1Ra but did not affect binding to either of the activating ligands IL-1a or IL-1b. This precluded the clinical use of recombinant IL-1Ra (anakinra), which is usually effective for IL-1-driven diseases, although IL-1b-targeting therapies were effective. Increasing the translational relevance of this finding, the study authors altered the therapeutic IL-1 trap rilonacept, a decoy receptor that neutralizes IL-1a and IL-1b but also binds to IL-1R1, potential reducing its efficacy. The altered agent, rilabnacept, still bound IL-1a and IL-1b but – due to the K131E mutation – did not target IL1R1. Hence, it more specifically targeted the proinflammatory IL-1 receptor ligands, enhancing its efficacy.
Phospholipase C gamma 2 (PLCg2) is an intracellular signaling molecule that converts PIP2 into DAG and IP3, causing Ca2+ release from the ER, which in turn triggers store-operated Ca2+ entry – a mechanism critical for pleotropic cellular functions including activation, proliferation, and development. APLAID is an inborn error of immunity caused by heterozygous gain of function mutations in PLCG2; patients develop autoinflammation, antibody deficiency and immune dysregulation 5,6. While IL-1 and TNF-targeting therapies are partially effective, no fully effective therapy has been described. Using a mouse model carrying a pathogenic APLAID mutation, Mulazzani et al found that elevation of G-CSF was the most distinguishing cytokine in affected mice and in patients with APLAID 6. Although G-CSF derived from non-hematapoietic cells, hematopoietic stem cell transplantation normalized the defect. In a separate study, Baysac et al described a novel form of monoallelic PLCG2 LOF and established that LOF mutations – like GOF mutations – are assocaitd with a high prevalence of inflammatory disease. It is not yet clear, however, whether G-CSF plays any role in the inflammatory disease associated with PLCG2 LOF 5.
Finally, this newsletter would be incomplete without addressing the expansion of chimeric antigen receptor (CAR) T cells to treat several autoimmune diseases in small but important clinical studies. CD19-targeted CAR T cells were originally developed to treat B cell malignancies, but landmark work in 2019 established their efficacy in murine autoimmunity models 7. A case report using CD19-CAR-T cells to treat a patient with refractory systemic lupus erythematosus (SLE) was reported in 2021, and a larger study of five patients was published in late 2022 by Mackensen et al 7,8. Antisynthetase syndrome is another severe and refractory autoimmune disease that comprises myositis, arthritis, dermatitis, and interstitial lung disease 9. Pecher et al used CD19 CAR T cells to treat a case of treatment-refractory antisynthetase syndrome, further validating this strategy as a treatment for B-cell-mediated autoimmune diseases 9. Granit et al targeted CAR T cells more specifically to plasmablasts by engineering them to target B cell maturation antigen (BCMA) in the treatment of myasthenia gravis 10. The authors engineered their CAR T cells with RNA (rCAR-T) to express the CAR transiently rather than permanently. This strategy was chosen to prevent amplification of the CAR signal during T cell proliferation, thereby reducing the risk of cytokine release syndrome. After receiving six BCMA-rCAR-T infusions, patients experienced clinically significant improvements in disease severity that were sustained for 9 months.
1 Baris, S. et al. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. J Allergy Clin Immunol 152, 182-194 e187, doi:10.1016/j.jaci.2023.01.023 (2023).
2 Sharma, M. et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J Exp Med 220, doi:10.1084/jem.20221755 (2023).
3 Baghdassarian, H. et al. Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome. N Engl J Med 388, 2241-2252, doi:10.1056/NEJMoa2202318 (2023).
4 Wang, Y. et al. Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design. Immunity 56, 1485-1501 e1487, doi:10.1016/j.immuni.2023.05.014 (2023).
5 Baysac, K. et al. PLCG2 associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants. J Allergy Clin Immunol, doi:10.1016/j.jaci.2023.08.036 (2023).
6 Mulazzani, E. et al. G-CSF drives autoinflammation in APLAID. Nat Immunol 24, 814-826, doi:10.1038/s41590-023-01473-6 (2023).
7 Schett, G., Mackensen, A. & Mougiakakos, D. CAR T-cell therapy in autoimmune diseases. Lancet, doi:10.1016/S0140-6736(23)01126-1 (2023).
8 Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124-2132, doi:10.1038/s41591-022-02017-5 (2022).
9 Pecher, A. C. et al. CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome. JAMA 329, 2154-2162, doi:10.1001/jama.2023.8753 (2023).
10 Granit, V. et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol 22, 578-590, doi:10.1016/S1474-4422(23)00194-1 (2023).