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Primary Immune Regulatory Disorders (PIRD)

What are primary immune regulatory disorders (PIRD)?

Primary immune regulatory disorders (PIRD) are a diverse group of rare genetic conditions in which the immune system does not respond appropriately to challenges or is not appropriately regulated in its responses. These changes can lead to underactive or overactive immune function. This is called immune dysregulation.

PIRD can affect multiple organ systems. These disorders can be caused by autoimmunity (a mistaken attack on healthy tissues or organs by the immune system), excessive inflammation (an overactive defense reaction by the immune system), and non-malignant lymphoproliferation (an abnormal increase in lymphocytes, a type of white blood cell). Patients usually begin to show symptoms early in life.

One example of a PIRD disorder is called IPEX syndrome, which stands for Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome. Patients can have severe watery diarrhea, skin rashes (eczema and other types), diabetes (inability to make insulin), low or high thyroid hormone levels, problems with low blood cell counts (anemia, low platelet counts, etc), and other problems. Each of these is caused by the immune system inappropriately attacking one of the organs of the body (autoimmunity).

Other clinical symptoms that are often seen in PIRD conditions include a progressive scarring of the lung tissue caused by immune attack of the lung (ie, interstitial lung disease), autoimmune hepatitis (liver inflammation), and arthritis (inflammation of the joints).

Unlike classical primary immunodeficiencies, patients with PIRD are typically at lower risk for infections. However, since patients can have autoimmunity and infections at the same time, these diseases can be very challenging to diagnose and treat. Many patients are undiagnosed, and the best treatment for individual disorders is not clear. Over the past decade, we have begun to understand the genetic causes of a growing number of these PIRDs, which is helping us learn how to treat PIRDs better.

Mutations (changes) in many different genes are now known to cause immune dysregulation. Some of these gene changes cause problems with the development or function of regulatory T cells (also called Tregs), which are a type of white blood cell that acts as a sort of peacekeeper (ie, regulators) for the immune system and is critical for maintaining control of immune responses.

For example, mutations in the gene called FOXP3 cause the regulatory T cells to not develop fully, leaving the immune system without important regulators. This is the cause of IPEX syndrome (see above). We now know that mutations in over 40 other genes can cause problems with the development or function of Tregs or other important types of white blood cells and can cause PIRD conditions with similarities to IPEX.

Initially, a PIRD diagnosis is based on clinical signs and symptoms. Autoimmunity that occurs early in life, is severe, and affects multiple organ systems may suggest the possibility of a PIRD. However, the best approach for early diagnosis is unknown at this time.

For certain types of PIRD, specific genetic testing is required to make a diagnosis. Genetic testing can often be very helpful in making a diagnosis of PIRD but may not find a specific gene mutation in every case. Care providers can perform gene testing by sequencing one gene or many genes at a time.

Sometimes, these tests can reveal new genetic mutations or variants, requiring further testing. In these cases, a combination of the following tests may help with diagnosis:

  • Measurement of key white blood cell types in blood including T cells, B cells, NK cells, and eosinophils, to see if the numbers are low, normal, or high.
  • Measurement of antibody (Immunoglobulin IgG, IgA, IgM, and IgE) levels in the blood. IgG, IgA, and IgM levels may be low, normal, or high, depending on the specific PIRD type. Often IgE levels are elevated.
  • Measurement of specific antibody levels to vaccines in the blood may detect a decreased ability to make immune responses to vaccines, in particular, the Pneumovax vaccine.
  • Measurement of Treg cells in blood may show abnormal numbers or function.
  • Detection of protein levels in blood or on blood cells is often insufficient. Tests to evaluate the function of blood cells may be required. These tests are usually available only in specialized research sites and not in clinical laboratories, which makes the diagnosis more difficult.

Treatment for PIRD varies depending on the disorder. Often, the severity of these disorders requires aggressive treatment to prevent long-term organ damage, disability, or death.

Treatments can include:

  • Supportive therapies, often the first line of treatment.
  • Medications (ie, tacrolimus, sirolimusa, batacept, JAK-inhibitors, TNF-inhibitors, etc) to decrease the immune response can help control symptoms and restore normal immune function in many cases.
  • Immunoglobulin replacement (IVIG or SCIG), for those with low IgG levels and/or poor antibody responses to vaccines and infections.
  • Hematopoietic cell transplantation (HCT), which can be curative for some PIRD disorders. There is limited information on HCT outcomes and there are many unanswered questions about the best approach at this time.