Too much of a good thing: a review of primary immune regulatory disorders

Abstract

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical ‘primary immunodeficiency’ as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research.

A case of primary immunodeficiency with immune dysregulation: features of clinical manifestation and diagnostic difficulties

“…Следует отметить, что спектр заболеваний с нарушением иммунной регуляции по мере появления новых данных, связанных с анализом различных фенотипов первичных нарушений иммунной регуляции и результатами анализа ДНК, значительно расширился в последние годы, и включает в себя различные аутоиммунные, аутовоспалительные, лимфопролиферативные синдромы в сочетании со злокачественными новообразованиями и аллергическими проявлениями. Учитывая разнообразие фенотипов и неполное проявление всех признаков первичного нарушения иммунной регуляции у конкретного индивидуума, клиницисты испытывают значительные сложности как в диагностике, так и в ведении пациентов с первичным нарушением иммунной регуляции, поскольку ТГСК может быть отстрочена из-за длительного процесса подготовки, до ТГСК клиницисту необходимо выдерживать баланс между высоким инфекционным риском и необходимостью иммуносупрессивной терапии, процедура ТГСК для пациента имеет свои риски, в том числе связанные с развитием реакции «трансплантат против хозяина» [10]. Особые трудности в диагностике первичных нарушений иммунной регуляции имеют место у пациентов первых месяцев жизни в силу неспецифичности клинических проявлений разнообразных заболеваний.…”

Infections in Disorders of Immune Regulation

“…While recent reviews have extensively covered the pathogenic mechanisms, clinical profiles, and management of common PIRDs [ 5 , 6 ], this review will specifically delve into the intricate relationship between infections and syndromes with autoimmunity. Including all immune dysregulatory disorders is beyond the scope of the review, so we have focused only on syndromes with autoimmunity with and without T regulatory defects.…”