The term “immune dysregulation” is a relatively new term to describe how the immune system dysfunctions by overreacting or underreacting to foreign assailants. Immunodeficiencies are categorized in two groups. Primary Immunodeficiencies are genetically determined. In 2019, the IUIS reported that 354 Inborn Errors of Immunity (IEI) and 430 genes have been linked to primary immunodeficiency disorders. The molecular basis of about 80% genetic errors is understood. Primary immunodeficiencies typically manifest during infancy and childhood as abnormally frequent or unusual infections. Because transmission is often X-linked, 60% are male. Overall incidence of symptomatic disease is about 1/280 people.
Inborn Errors of Immunity is further categorized into two classes, one is called Primary Immune Deficiency Disorders (PIDD), which is 70% of 430 causative genes, the other 129 genes (30%) are categorized as Primary Immune Regulatory Disorders (PIRD), the latter is due to Immune Dysregulation which is dysfunction of molecules regulating the immune system. The clinical manifestations of PIRD predominantly result from an immune-mediated pathology rather than severe or recurrent infections. A breakdown in immune regulation results in clinical phenotypes such as autoimmunity, autoinflammation/hyperinflammation, lymphoproliferation, malignancy, and severe atopy.
Immunodeficiencies acquired after birth are called Secondary Immunodeficiency. Secondary immunodeficiency may occur in patients who receive chemotherapy or radiation treatment (immunosuppressive treatments), or diabetes, or are malnourished, or have an HIV infection, or older patients with chronic illnesses. The foregoing illnesses may impair immune responses and present immunodeficiency pathology such as the kidneys with nephrotic syndrome, severely burned skin, or dermatitis, and enteropathy of the gastrointestinal tract. These conditions could result from loss of serum proteins such as IgG or albumin.
IPEX syndrome
One of the prototype of PIRD is, Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome. Mutation in the FOXP3 gene, which encodes a major transcription factor of regulatory T cells (Tregs) in IPEX syndrome leads to dysfunctional Tregs, and as a result cause autoimmune diseases. The clinical manifestations of IPEX syndrome are enteropathy, type I diabetes mellitus, thyroiditis, autoimmune-mediated cytopenia, and eczema. In addition to autoimmune disease symptoms, IPEX patients experience higher immune reactivity such as chronic dermatitis and susceptibility to infections. Other genes manifest similar symptoms to IPEX leading to dysfunction of Tregs are CD25, CTLA4, LRBA, DEF6, IL2RB, STAT1, 3, 5B.
Wiskott-Aldrich Syndrome
Wiskott-Aldrich Syndrome (WAS) is caused by a mutation in the WAS gene. It manifests itself as a higher susceptibility to infections, eczema, more frequent development of autoimmune hemolytic anemia, neutropenia and arthritis. The protein from WAS gene is WASp, expressed exclusively in hematopoietic cells, showing signaling and cytoskeletal abnormalities in WAS patients. In WAS patients usually WASp protein is significantly reduced or absent. Mutations of WAS gene in WH1 domain affects binding of WASp with WASp Interacting Protein (WIP) and interfere following signaling, causing X-linked thrombocytopenia, and small-sized platelets due to impaired maturation of platelets. In addition, impairment of WASp and Calcium- Integrin- binding protein (CIB) binding leads to disturbance of aIIbb3-integrin mediated cell adhesion, causing defective platelet aggregation and resulting in bleeding. On the other hand, mutations in the GBD domain of the WAS gene disrupt “autoinhibition” of WASp, since WASp is usually folding and inactivating itself, then the mutation leads to unfold WASp (open), constitutively active. Activated WASp leads to nuclear localization of actin filaments and this leads to premature apoptosis, aneuploidy and failure to undergo cytokinesis, ending up in myelodysplasia and X-linked neutropenia. Altered Core2 glycan structure from WAS patient T-lymphocytes is linked to underdevelopment of T-cells and leads to reduced immune response .
Other genetic error Immune Dysregulation diseases
Primary Immune Regulatory Disorders comprises a broad range of diseases in defects of various immune regulatory pathways. IPEX and IPEX-like diseases are called Tregopathies which are defects in Treg cells.
Exaggerated innate and adaptive inflammatory responses can develop autoinflammatory syndromes and hyperinflammatory disorders, and congenital atopic hypersensitivity. Causative genes of these diseases include, Tumor Necrosis Factor Receptor associated proteins (TNFRSF1A, 11A), and CDC42, NLRP3, MEFV, ADA2, IL1RN, RIPK1, LYST, ITK, MAGT1, NLRC4 etc..
Mutations in CASP10 or FAS-ligand causes uncontrolled immune cell activation and proliferation leading to Non-malignant Autoimmune Lymphoproliferative Syndrome (ALSP). Mutations in K-RAS or N-RAS genes causes lymphoproliferation but are non-malignant. Defects in HAVCR2, STAT3-GOF, CARD11, GATA2 genes will lead to malignant leukemia or lymphoma, such as subcutaneous panniculitis-like T-cell lymphoma, large granular lymphocytic leukemia, diffuse large B-cell lymphoma, acute myeloid leukemia.
The other categories include monogenic inflammatory bowel diseases (IBD) which is caused by dysfunction in the intestinal immune regulation, and rheumatologic diseases which arise from a breakdown in self-tolerance. These are examples of 129 Primary Immune Regulatory Disorders genes.
T-cell immunodeficiency
Partial T cell immunodeficiency is characterized by an incomplete reduction in T cell numbers or activity. T-cell immunodeficiencies could be associated with autoimmune diseases or hyperactivity and increase IgE production. Mutations are found in genes for cytokines (such as IL-7), TCRs, or proteins important for somatic recombination and antigen presentation.
Additional T cell-associated immune dysregulation is a mutation in CTLA-4. CTLA-4 is essential for the negative regulation of the immune response and its loss leads to dysregulation and autoimmune diseases. The disease is characterized by hypogammaglobulinemia, frequent infections and the occurrence of autoimmune diseases. In individuals, the disease may manifest itself differently, in some cases only a partial reduction in the number of Tregs, in others the ability to bind CTLA-4 ligand has been reduced, resulting in disruption of homeostasis of effector T and B cells. The inheritance of this syndrome is autosomal dominant with incomplete penetration.
DAMP-sensing receptors in inflammatory diseases
The innate immune system has the capacity to detect “non-self” molecules derived from pathogens. In addition, endogenous host-derived molecules from damaged cells and tissues, termed “damage-associated molecular patters (DAMP)” have been sensed by DAMP-sensing receptors. Impairment of DAMP-sensing receptors leads to dysregulation of sterile (non-infectious) inflammation, causing inflammation, autoimmune diseases and cancer.
Examples of DAMP-receptors are, Toll-Like Receptor (TLR)-2, 3, 4, 7, 9. In the ischemia-reperfusion injury (IRI), the injury induces vast DAMP release, activate TLR-4, 2, 3 and cause excessive systemic inflammatory responses. In another example, in systemic lupus erythematosus (SLE), internalized self-nucleic acid bound antibodies (DNA, RNA and protein complex) can be internalized by Fcg receptors on plasmacytoid dendritic cells and stimulate those to produce IFN-a in a TLR-9 and TLR-7 dependent manner. In the case of rheumatoid arthritis (RA), the glycoprotein Tenascin-C in the extracellular matrix was shown to induce TLR-4 activation and pro-inflammatory cytokine production, mediating persistent inflammation and tissue destruction.
Aging of the immune system
Dysregulation of the immune system is also associated with immunosenescence (the changes in the immune system associated with age), which arises due to aging. In this category, without particular genetic mutations, the immune systems gain maturation and exhaust system as follows.
Immunosenescence is manifested by a decrease in reactivity to vaccination or infection, an impaired ability of T and B lymphocytes to activate and proliferate, or a lower ability of antigen presentation by dendritic cells. In immunosenescence, memory and effector Treg cells accumulate at the expense of naïve T cells, causing low plasticity in the elderly. In aging of the immune system, the central tolerance is also decreased, and the number of autoreactive T cells are increased. B cells have a decreased repertoire of naïve cells and memory B cells are accumulated; antibody production is also reduced. The overall accumulation of both effector T and B cells is due to the presence of chronic inflammation by long term exposure to antigens.
Innate immunity cells are also affected in immunosenescence. NK cell reactivity and the antigen presentation by dendritic cells are impaired. The ability of macrophages to induce phagocytosis is reduced. The production of some immune mediators is increased, such as pro-inflammatory IL-6 or IL-1, and anti-inflammatory IL-10 or IL-4.
Microglia
Microglia, the main player of neuro-immune system, has three essential functions: constant sensing of changes in the environment (brain and neuronal system), housekeeping function promoting normal neuronal operation, and defense function necessary for responding to changes and provide neuroprotection. However, in response to specific stimuli, or with neuroinflammation, microglia have the capacity to damage and kill neurons. Injuries to neurons are apparent in Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as in Multiple Sclerosis, Amyotrophic Lateral Sclerosis, frontotemporal dementia, or chronic traumatic encephalopathy and are a result of disruption of microglia functions.
For example, microglia digests aggregated self-protein Ab by phagocytosis. Decreased clearance of Ab by microglia may lead to Alzheimer’s disease (AD). This is the same situation regarding a-Synuclein protein clearance in Parkinson’s disease. In addition to Ab clearance in AD, microglia-Ab interactions mediated by DAMP-receptors including TLRs lead to early synapse loss, production of neurotoxic reactive oxygen species (ROS) and production of inflammatory cytokines and TNF.
The pathways associated with neuronal injuries in microglia include Trem2, Cx3cr1, and progranulin pathways, which function as immune checkpoints to keep the microglial inflammatory response under control, and scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation of the gut microbiome can also alter progression of such injury. Correcting such imbalance of microglial functions may be a potential target for therapy.
Taken together Immune system is regulated by hundreds of important molecules. Disruption of one of these molecules leads to immune dysregulation and cause serious immunodeficiency, autoimmune diseases, or inflammatory diseases.
Written by: Misa S. Anekoji, Ph. D.
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