November 10-15

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Rare Inborn Errors of Immunity Can Inform More Common Autoimmune Diseases


5 minutes

Inborn errors of immunity can shed light on the inflammatory pathways common to many rheumatic diseases. These disorders are rare, monogenic diseases that often present with a variety of immune-related symptoms, including increased susceptibility to infection, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and increased risk of malignancy.

Four experts in the field discussed their work on extrapolating insights on the mechanisms of specific inborn errors of immunity to more common diseases during Complex Inborn Errors of Immunity: Lessons and Implications for Common Rheumatic Diseases. The session is available on demand for registered ACR Convergence 2023 participants through October 31, 2024, on the meeting website.

Daniel Kastner, MD, PhD
Daniel Kastner, MD, PhD

“Monogenic diseases can teach us a lot about more common illnesses caused by combinations of low-penetrance variants,” said Daniel Kastner, MD, PhD, National Institutes of Health (NIH) Distinguished Investigator, National Human Genome Research Institute. “But the associated phenotypes may differ substantially. It’s not as if rare diseases are a replica of the common disease.”

A 2022 publication from the International Union of Immunological Societies Expert Committee lists 485 human inborn errors of immunity, though Dr. Kastner noted that the list has probably increased since then.

He gave an overview of the landscape of inborn errors of immunity, highlighting three categories — immunodeficiencies, autoimmunity, and autoinflammatory diseases — and how they demonstrate basic principles of how the immune system works.

For example, work on autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which is caused by mutations in the autoimmune regulator (AIRE) gene, has provided insights into T cell tolerance. Studies of patients with Mendelian susceptibility to mycobacterial diseases (MSMD) have helped researchers better understand the role of type 1 interferons and interferon-gamma.

Gulbu Uzel, MD
Gulbu Uzel, MD

Gulbu Uzel, MD, Senior Research Physician, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), discussed her work on how mutations in cytotoxic T lymphocyte antigen 4 (CTLA-4) has yielded insights into T cell-mediated autoimmunity. CTLA-4 is a well-characterized receptor found on the surface of regulatory T cells, which help to suppress immune activity.

“Regulatory T cells help to put the brakes on the immune system,” said Dr. Uzel. “This is broken when you have lower CTLA-4 expression due to mutation in one of the alleles.”

Patients with CTLA-4 deficiency have fewer regulatory T cells — and those that they do have are often dysfunctional. This leads to autoimmunity and an increased predisposition to malignancy.

Yet not everyone with CTLA-4 variants experiences symptoms. Dr. Uzel presented the case of a patient with CTLA-4 deficiency who experienced multiple autoimmune problems, including common variable immunodeficiency, interstitial lung disease, psoriasis, and chronic gastritis. His brother, who carried the same mutations, was symptom free.

Dr. Uzel is studying a cohort of more than 100 patients with CTLA-4 deficiency across nearly 50 families to better understand the spectrum of clinical symptoms. Her group has identified multiple mutations across the CTLA-4 gene that render the CTLA-4 receptor dysfunctional.

Researchers have defined the spectrum of CTLA-4 deficiency disease based on clinical symptoms — from asymptomatic to limited autoimmunity and multisystem involvement. They are interested in better understanding the factors that protect asymptomatic individuals.

Daniella Schwartz, MD
Daniella Schwartz, MD

Daniella Schwartz, MD, Assistant Professor of Medicine, University of Pittsburgh, discussed her work on haploinsufficiency of A20 (HA20). 

HA20 is caused by variants in the tumor necrosis factor alpha induced protein 3 (TNFAIP3) gene and is marked by multiple types of immune dysregulation, from immunodeficiency to autoinflammation, allergy, lymphoproliferation, and autoimmunity.

 “We often think of discrete types of immune dysregulation, but we see all of this in HA20,” Dr. Schwartz said. “It crosses all these boundaries and can look extremely heterogeneous, even in the same family.”

Part of the reason why HA20 results in so many phenotypes is that it is expressed in multiple immune cell types and has many molecular functions, including roles in apoptosis, necroptosis, interferon signaling, and inflammasome activation.

Polymorphisms in A20 are also associated with a range of common rheumatic diseases, including lupus, scleroderma, and Sjogren’s syndrome. In many cases, these polymorphisms are associated with reduced A20 function or expression, which Dr. Schwartz notes may be functionally relevant.

“We are beginning to believe that there is a spectrum of A20 insufficiency,” Dr. Schwartz said. “There are patients with true haploinsufficiency, there are patients with common variants, and there is a lot in the middle.”

Carrie Lucas, PhD
Carrie Lucas, PhD

Carrie Lucas, PhD, Associate Professor of Immunobiology, Yale University, discussed her research on deficiency in ELF4, X-linked (DEX), a monogenic autoinflammatory disease caused by mutations in ELF4.

Patients with DEX exhibit multiple symptoms reminiscent of Behçet’s syndrome — recurring fevers, abdominal pain and diarrhea, and aphthous ulcers throughout the mouth and gastrointestinal tract. Dr. Lucas is working with a small cohort of patients with DEX to better understand the spectrum of clinical phenotypes.

ELF4 is a transcription factor with known roles in lymphocytes and NK cell development that couldn’t explain the phenotypes of patients with DEX.

Dr. Lucas’s group has shown that patients with DEX have heightened Th17 cell responses. These inflammatory T cells play a role in clearing pathogens but are also implicated in several autoimmune diseases.

Further investigation into the role of ELF4 in T-cell function revealed that ELF4 resides in the nucleus of naïve CD4-positive T cells and is important for regulating the integrated stress response. Upon T cell activation, ELF4 is downregulated, leading to a dampening of inflammatory T cell responses.

“We think that ELF4 naturally functions as a brake in T cells,” she said. “When the cell wants to release that brake, it downregulates ELF4.”

Understanding the mechanism of ELF4 activity may prove to be relevant to other inflammatory diseases. Dr. Lucas noted that three variants in the ELF4 gene have been associated with ulcerative colitis.

“We would predict that in some patients with inflammatory bowel disease (IBD), there may be variants that impact the expression level of ELF4,” said Dr. Lucas. “That could contribute to their susceptibility to IBD, but this remains to be proven.”


If you weren’t able to attend a session in person during ACR Convergence 2023, you haven’t missed out. All registered meeting participants receive on-demand access to scientific sessions through October 31, 2024.