A healthy GI tract needs robust interaction between the gut, skin barrier function, the immune system, and the microscopic living organisms of the gut (the gut microbiome). Dysregulation or deficiency in any compartment of the immune system, such as neutrophils, T and B cells, and macrophages, can cause colitis and enteropathy in children. While colitis is associated with inflammation in the GI tract and painful, often bloody, bowel movements, enteropathy is associated with an autoimmune response that leads to large-volume, watery bowel movements. Both can be associated with poor weight gain and failure to thrive.
Depending on what causes the underlying immune dysregulation and inflammation, GI tract colitis in PIRD can be classified as:
This group has a genetic variant that results in either decreased T regulatory cell numbers or function. T regulatory cells are a subpopulation of T cells that control the immune system by maintaining tolerance to self-tissues and preventing autoimmune disease.
Immune dysregulation, endocrine failure, and enteropathy in an X-linked inheritance pattern (IPEX) syndrome is the prototype of this group. Several other immunodeficiencies (IPEX-like) with functional T regulatory cell defects are also associated with autoimmune enteropathy.
In all these conditions, the functional deficiency of T regulatory cells leads to unchecked T cell activation. This results in autoimmune disease against cells in the intestines, as well as other parts of the body.
Chronic granulomatous disease (CGD), which is a form of primary immunodeficiency disease characterized by defects in neutrophil function, is a prototype of this group. Individuals with CGD can present with varying severity of colitis and perianal disease.
GI inflammation due to excess proinflammatory signals from the macrophages has been proposed to be the primary driver of inflammatory bowel disease (IBD) in infants and children with genetic variants in IL-10 and IL-10R.
Excess inflammation due to variants in critical proteins involved in the inflammatory cascade can also lead to GI inflammation and colitis.
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To diagnose underlying PIRD with colitis, a combination of immune and genetic testing is warranted in most individuals. Immune studies look at the number, proportion, activation status, and functional status of the different immune cells. Immune studies could give a clue to the nature of immune dysregulation and, in some cases, clues to possible underlying genetic variants.
Increasingly, genetic studies are being done upfront for most individuals. Instead of testing one gene at a time, most physicians now rely on gene panels (usually ten to several hundred genes) that include the genes that are likely to result in immune dysregulation. If the gene panel is negative, several clinical centers will proceed to whole exome sequencing, wherein all the genes known to cause human disease are looked at. When whole exome sequencing is done, samples from the parents are often requested to improve the diagnostic accuracy.
The genetics and mode of inheritance of PIRD presenting with colitis are varied. It is important to realize, especially with autosomal dominant inheritance, that more than one family member might be affected with the same genetic variant. The severity and the age of onset are variable with family members with the same genetic variant. De-novo variants (neither of the parents are carriers of the variant) are known to cause some PIRD.
The process of diagnostic immune and genetic evaluation is time-consuming. In some individuals, there is a development of more autoimmune or infectious symptoms over months to years. Colitis can be an early presenting symptom of underlying immune dysregulation or a late presentation that follows other autoimmune complications. Despite extensive immune and genetic evaluation, a significant majority of individuals with immune dysregulation might not have a genetic diagnosis. However, every year, variants in new genes are being identified that cause immune dysregulation; in the future, we expect a higher percentage might have a recognized genetic basis.
Additionally, since these individuals' GI inflammation might differ, they may not have a positive response to traditional first and second-line IBD therapy (anti-TNF agents). In some nonclassical IBD, treatment addressing broader immune dysregulation might be a better approach. If the immune and genetic basis is identified and medical management alone results in a poor response or if the treatment has significant side effects limiting the long-term options, HSCT to correct the underlying immune defect might be an option.
If an underlying genetic variant is identified, genetic counseling to identify other family members with a carrier or disease state might be recommended. Additionally, for parents who are carriers of genetic variants, genetic counseling and techniques such as in-vitro fertilization and pre-implantation genetics could give an option of having a healthy child.
This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.
Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition.
Copyright ©2019 by Immune Deficiency Foundation, USA
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