Advanced Course in Immunology On Demand Lecture Recordings-Redefining Human Immunology: Lessons from Inborn Errors of Immunity

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Video Summary

The speaker, a pediatric rheumatologist and immunologist, described how studying patients with monogenic immune disorders has revealed key principles of human immunity and enabled precision treatments. She highlighted the wide diversity of inborn errors of immunity through several cases: X-linked agammaglobulinemia due to BTK loss, CARD11 dominant-negative disease causing immune deficiency and eczema, APDS from PIK3CD gain of function treated with mTOR or PI3Kδ inhibition, and IL-10 receptor deficiency causing severe early inflammatory bowel disease treated with IL-1 blockade and stem cell transplant.<br /><br />She then focused on lessons in immune tolerance. AIRE deficiency (APS-1) illustrates failure of central T-cell tolerance and causes multiorgan autoimmunity, while FOXP3 deficiency (IPEX) reflects loss of regulatory T cells and often requires hematopoietic stem cell transplantation. She also discussed checkpoint pathway disorders such as CTLA-4, LRBA, DEF6, and PD-1 deficiency, which demonstrate the importance of peripheral tolerance and predict toxicities seen with checkpoint blockade cancer therapy.<br /><br />Next, she reviewed primary immune regulatory disorders involving JAK-STAT signaling. Gain-of-function variants in STAT1, STAT3, STAT4, STAT6, and JAK1, as well as loss of function in negative regulators like SOCS1 and PTPN2, produce distinct patterns of autoimmunity, allergy, inflammation, and lymphoproliferation. Many patients benefit from targeted therapies, especially JAK inhibitors.<br /><br />Finally, she discussed why many cases remain unsolved: structural variants, non-coding changes, cytokine autoantibodies, monolelic expression, and somatic mosaicism. Her main message was that rare immune diseases are powerful tools for discovering immune pathways and improving patient care.

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Lecture 22: Megan A. Cooper, Washington University School of Medicine

Redefining Human Immunology: Lessons from Inborn Errors of Immunity

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Megan A. Cooper, Washington University School of Medicine
Redefining Human Immunology: Lessons from Inborn Errors of Immunity

Keywords

monogenic immune disorders

inborn errors of immunity

BTK deficiency

CARD11

PIK3CD

IL-10 receptor deficiency

AIRE deficiency

FOXP3 deficiency

CTLA-4

JAK-STAT signaling

JAK inhibitors

immune tolerance