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In When Immune Deficiency and Autoimmunity Coexist, a session at the 2018 ACR/ARHP Annual Meeting, M. Eric Gershwin, MD, the Jack and Donald Chia professor of Medicine and chief of Rheumatology, Allergy and Clinical Immunology at the University of California, Davis, School of Medicine, Sacramento, discussed autoimmunity in a subset of patients with primary immune deficiencies and how to manage these complex conditions.
Rare & Rarer
Over the past 50 years, research has revealed a higher incidence of autoantibodies and disease in patients with primary immune deficiency, such as Wiskott-Aldrich syndrome.1 In this very rare immune deficiency disease, patients are less able to form blood clots. They are at higher risk of developing rheumatoid arthritis (RA) and hemolytic anemia. Why do these links exist? Clues may lie in the patient’s genes, as well as how genes are methylated, said Dr. Gershwin.
“There are about 300 [primary immune deficiencies] recognized at this time, and most are caused by genetic abnormalities,” he said. “They involve an inherent deficiency in the innate and/or adaptive components of the body’s immune response.”
To identify patients with primary immune deficiencies, “the things I look for are documentation of repeated sinus infections. Not sinusitis or ‘my head hurts,’ but a sinus image that is repetitively abnormal. Look for repetitive episodes of pneumonias, and persistent infections that just don’t seem to resolve. Those are the major hallmarks,” along with thrush and family primary immune deficiency history, said Dr. Gershwin.
Due to earlier diagnosis and treatment with intravenous immunoglobulin, as well as bone marrow transplantation or stem cell transplantation, patients with primary immune deficiency now live longer. Therefore, physicians are detecting complications later in life, including autoantibodies and autoimmune disease, and the primary immune deficiency/autoimmunity combination presents treatment dilemmas for the physician.
Common variable immune deficiency (CVID), which affects about one in every 25,000 Caucasians, is the most common primary immune deficiency.2 CVID patients have marked serum reductions in both IgG and IgA, and about half have reduced IgM. Additionally, if IgA and IgM are also low, this combination is a strong sign of CVID.
The disease affects both men and women equally. Often, CVID patients present with upper airway infections, followed by infectious diarrhea and septic arthritis. But they may also have autoimmune diseases: hemolytic anemia, autoimmune thyroid disease, RA and juvenile RA. They may also have enlarged lymph nodes and spleens, as well as bronchiectasis. Patients may have an increased risk of gastric carcinoma, most commonly due to co-infection with H. pylori, said Dr. Gershwin.
Signs of CVID include multiple bacterial or viral infections in a short period of time, poor response to antibiotics, reduced immunoglobulin levels and reduced immune response after vaccinations. But an enormous variation may exist between these patients, said Dr. Gershwin. Cytopenia, bronchiectasis or granuloma, other inflammation or autoimmune diseases are other clues. And in 17.4% of patients, CVID diagnosis comes after the autoimmunity diagnosis.
“There’s no correlation between the presence of autoimmune phenomena in a patient with CVID and its severity,” which may have to do with the genetic basis of the disease, he said. CVID appears both in young children and adults and is a diagnosis of exclusion that is often delayed for years.
In CVID, patients may have a multiplicity of immune cell defects, and each person has different symptoms, complications and disease progression, said Dr. Gershwin. “Perhaps this syndrome, more than almost any other immune deficiency, reflects that it is variable, because it is not one disorder. It represents a multiplicity of disorders all sharing one thing in common: inefficient production of antibodies accompanied by recurrent infections. As we begin to unravel the genetic basis of this disease, individualized, personalized therapy will hopefully improve for these patients.”
Cheaper DNA sequencing has led to the identification of more genetic defects in CVID, but clearly complex, interconnected pathways are at play that are both epigenetic and Mendelian in origin, he said. Although 90% of CVID patients manifest with infections, between 26–30% have autoimmunity.
“So what’s the link? The defect may be closely related to a common susceptibility locus, and it could be that a persistent, opportunistic infection leads by way of molecular mutation that may skew the body toward either a Th1 or Th2 response,” said Dr Gershwin. “There may be incomplete clearance of a pathogen that ultimately leads to some deviation from the immune system or an increased load of apoptosis, leading to an abnormal antigen presentation, increased immune complexes, bystander activation and, ultimately, autoimmunity.”
Multiple familial and environmental factors may influence the immune system in CVID, noted Dr. Gershwin.
“It’s possible that the defect that causes CVID may tilt the immune system toward loss of tolerance and breach of tolerance,” he said. “I can’t give you the reason why someone with primary immune deficiency ends up with autoimmunity. What I can tell you: In patients with CVID, a common variable is abnormal B cell homeostasis.”
Abnormal B cell function leads to loss of tolerance and reduced autoantibodies in these patients, who also, often, have lymphopenia, expansion of CD8 T lymphocytes and reduced thymic output.
Additionally, significant abnormalities exist in a number of T cells in patients with CVID, so much so that some experts believe it is a disease of T cells or that CVID’s B cell defects are a product of T cell deficiency.
“These patients are at much greater risk of defects in adaptive immunity. Interestingly, you cannot have an abnormality in an adaptive response without a corresponding defect in innate immunity. They move together,” said Dr. Gershwin. “Most [primary immune deficiencies] are those of adaptive immunity. The minority are of innate immunity. The reason for that may be that defects of innate immunity may be a fatal disease, and there may even be loss in utero.”
The most common autoimmune diseases associated with CVID are hematologic, although the reason is unclear, he noted. In both men and women with CVID, survival is significantly reduced due to any one of multiple complications, such as lymphoma, hepatitis, structural or functional lung impairment or gastrointestinal disease with or without malabsorption. However, in studies of CVID, autoimmunity was not associated with mortality.
Dr. Gershwin compared developing CVID therapies with plugging a leak in a dike: Plug one leak and other leaks may emerge as a result.
“The immune system is very smart. As we know from lupus and the failure of multiple drugs that seemed to have worked in mice; as soon as you put them in a human, you block the pathway you intended to block, but the promiscuous autoimmune response finds another way around that. Then you wind up with autoimmunity through a different route,” he said. Physicians must educate patients so they can quickly seek care for high fevers and other signs of serious infection.
About 80% of patients with CVID have defects in multiple genes, and the long list of culprits includes NFKB1, TNFRSF7 (CD27), PIK3R1 and CD19. As the cost of gene sequencing comes down, physicians may be able to detect these defects quickly and early in life. Dr. Gershwin said, “I believe that there will come a time in America that when a child is born, they’ll get a social security number and also an email address, a cell phone number, and get their DNA sequenced.”
In a small number of CVID patients who survived bone marrow or stem cell transplantation, 50% were cured of their immunodeficiencies, while the other half still had various forms of immunodeficiency, said Dr. Gershwin. This finding suggests contributing factors to CVID’s origin may lie outside the hematopoietic system.
Epigenetics may offer clues about loss of tolerance in CVID. In one study, DNA methylation patterns in monozygotic twins were discordant for CVID.
“We do know that as those B cells start to mature, the methylation on those B cells remains hyper compared with normal individuals. There is some inherent defect in methylation status of patients with a common variable,” said Dr. Gershwin.
First-line treatment for CVID is lifelong immunoglobulin replacement, either subcutaneous or intravenous. The most common complications are immune thrombocytopenia and autoimmune hemolytic anemia. Treatments for CVID patients with autoimmunity include an array of immunosuppressants, including biologics.
Another primary immune deficiency that may overlap with autoimmune disease is IPEX, which stands for immune deficiency, polyendocrinopathy, enteropathy, X-linked inheritance.4 IPEX, as in a number of other primary immunodeficiencies, is caused by defects on the X chromosome.
IPEX is caused by a defective FOXP3 transcription factor gene, which leads to a reduction in T regulatory cells, which then leads to immune dysregulation and loss of tolerance. Children with IPEX will die if they don’t have bone marrow transplants, said Dr. Gershwin.
T regulatory cells express FOXP3, which is critical in the transfer of immune tolerance, especially self-tolerance. Also, a related primary immune-deficiency, IPEX-like disease is found in females who have defective T regulatory cells caused by mutations in the IL2r (CD25) or signal transducer and activator of transcription (STAT) genes.
The effect of individual IPEX mutations on FOXP3 expression and function is variable, said Dr. Gershwin. “Any mutation of the functional area of the molecule has implications downstream. And this is best illustrated by IPEX: 60 unique mutations have been recorded of the FOXP3 gene. The [effect] of these mutations on the individual is like a crapshoot. It’s not always predictable,” he said.
IPEX disease severity and symptoms may vary considerably between even two patients with the same gene mutation, which suggests severity may be modulated by other disease-modifying genes that affect T regulatory cell function, as well as variability in the T cell receptor repertoire, the major histocompatibility complex haplotype or epigenetic and environmental factors.
Patients with IPEX have enteropathy that usually presents as intractable diarrhea. Because of defects in their T regulatory cell function, these patients have no control of complex gut immune components.
“If you don’t have FOXP3, you won’t have normal thymic selection,” said Dr. Gershwin. “Thymic selection, the forbidden clone, is the key to understanding how loss of tolerance takes place at least in some cases.”
Without functional FOXP3 and with impaired T regulatory cells, these patients’ checkpoints for self-immune education are disrupted. Often, patients with IPEX have type 1 diabetes and thyroid-associated immune disorders that may be diagnosed shortly after birth. T regulatory cells also play a role in controlling skin lesions. IPEX patients may present with atopic dermatitis and psoriasis, as well as skin rashes that are reactions to food allergies, which are common. They often have prolonged elevated IgE levels.
Immunosuppressants may be used to control IPEX symptoms, but hematopoietic stem cell transplantation, which requires a donor match, is the only effective treatment for the underlying disease.
In the future, research may point to ways to diagnose patients with primary immune deficiencies and autoimmunity earlier and improve first-line therapy, said Dr. Gershwin.
“Obviously, early diagnosis helps patients: It helps them prevent infection and helps in their bronchiectasis,” he said. “We may have more effective immunoglobulin treatment, maybe with longer half-life or more functionality. And of course, if we ever really knew the exact link, we [might] be able to have a bull’s eye-specific focus on how to treat those aspects of autoantibodies in autoimmune disease before they happen in patients with immune deficiency.”
Susan Bernstein is a freelance medical journalist based in Atlanta.
- U.S. Department of Health and Human Services. National Institutes of Health: Genetic and Rare Diseases Information Center. 2018
- Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol. 2008 May;28(Suppl 1):S42–S45.
- Rodriguez-Cortez VC, del Pino-Molina L, Rodriguez-Ubreva J, et al. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B cell transition. Nat Commun. 2015 Jun;6:7335.
- Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: A paradigm of immunodeficiency with autoimmunity. Front Immunol. 2012;3;211.