Primary Immunodeficiencies Lecture Notes lec 17

Primary Immunodeficiencies

Introduction

• David from the Kirby Institute presents the lecture on primary immunodeficiencies.

• Dr. Cynthia Munier will present on secondary immunodeficiencies.

• Primary immunodeficiencies: Definition, classification, examples (biological or genetic origin), infections, reasons behind infections (direct or indirect), typical and prospective treatments.

The Immune System and Primary Immunodeficiencies

Overview

• The immune system is powerful and complex, with multiple levels to prevent opportunistic infections.

• Spot checks (biological or genetic) limit unwanted responses.

• Primary immunodeficiencies are disorders affecting the immune network, stemming from biological or genetic sources.

• These deficiencies can affect the regulation of the immune network.

• They are rare and can result in a range of immunopathology, from mild to severe.

• Some severe cases are screened for at birth (e.g., severe combined immunodeficiency disorder).

Diagnosis and Complexity

• Diagnosis is faster and more accurate through genomic sequencing, which identifies single nucleotide variants (SNVs) and insertions/deletions (indels).

• Epigenetics adds another layer of complexity.

Symptoms and Infections

• Symptoms can present early or late, varying from weight loss and failure to thrive in infants to specific pathologies like ear infections, rashes, and skin infections.

• Infections can occur in the mouth (thrush), reproductive canal, oropharynx, and pulmonary tissues (pneumonia, bronchitis).

• These infections may not respond well to standard antibiotic or antiviral treatments.

Immune Cell Function and Primary Immunodeficiencies

Immune Cell Function

• Innate or adaptive immune cells may not function properly.

• The anatomy pathway, complement, and pattern recognition receptors (e.g., toll-like receptors) detect and neutralize pathogens.

• Adaptive immunity, specifically B and T cells (CD4 and CD8 T cells), coordinates and executes immune responses.

Maturation Processes

• Maturation processes of adaptive immune cells require careful monitoring to prevent autoimmune disorders.

• Spot checks to eliminate cells with the wrong affinity don't always work.

Prevalence and Inheritance

General Statistics

• Most primary immunodeficiencies relate to antibody deficiencies, followed by T cell immunodeficiencies, phagocytic defects, and complement protein deficiencies.

• Primary immunodeficiencies are rare, averaging around 1 in 10,000 births.

• Severe combined immunodeficiency disorder affects about 6-8 patients in Australia per year.

• IgA deficiency is more common, affecting 1 in 500 individuals.

Inheritance Patterns

• These conditions are inherited or sporadic, depending on the inheritance pattern and parental origin.

• Mutations are a part of life, but when they present as immunodeficiencies, they provide insight into immune system function.

Origin of Primary Immunodeficiencies

• Stem cells differentiate into either the innate lineage (myeloid progenitor cells) or the adaptive immune lineage (lymphoid progenitor cells).
  

Lymphoid Progenitor Pathway

*Focus predominantly on the lymphoid progenitor pathway. Lymphoid progenitor cells become B cells (critical for immunity) and T cells.

*Activated B cells become plasma cells, releasing antibodies (small proteins, ~150 kilodaltons for IgG).

*Antibodies bind pathogens, opsonize them, and facilitate their recognition and processing, thus leading to extermination.

B Cell Deficiencies

Infections and Symptoms

• Defective or absent antibody production leads to opportunistic infections such as influenza, staphylococcus, streptococcus, pneumonias, pseudomonas.

• Infections typically occur in mucosal surfaces (oropharynx, pulmonary, gastrointestinal tracts), causing sinusitis, diarrhea, etc.

• Symptoms may not be apparent early in breastfed infants due to antibodies in colostrum.

X-linked Agammaglobulinemia

• X-linked agammaglobulinemia is more common in males due to having only one maternal X chromosome copy.

B Cell Maturation

Maturation Process

• B cells mature in the bone marrow, undergo selection, and circulate in the periphery if properly signaled via the B cell antigen receptor.

• Final maturation occurs in the spleen.

• The process aims to create a non-reactive but immune-competent repertoire, deleting self-reactive responses.

X-linked Agammaglobulinemia Mechanism

• X-linked agammaglobulinemia results from a Bruton's tyrosine kinase (BTK) mutation, leading to a lack of an enzyme essential for B cell development.

• This blocks the pre-B cell to immature B cell stage transition.

• Treatment involves monthly immunoglobulin infusions.

• The BTK mutation is on the long arm of the X chromosome, affecting immunoglobulin production.

Selective IgA Deficiency

General Information

• Very limited or no IgA is present.

• IgA is a dimeric antibody designed for secretion across mucus membranes and lasts longer than six days.

• Found in tears, saliva, colostrum, genital region, lungs, and gastrointestinal secretions.

• Promotes opsonization and regulates gut inflammation.

• Different from IgM and IgG, which eliminate pathogens in vivo (bloodstream).

• Those with selective IgA deficiency may also be deficient in IgG and IgM, but other antibodies can compensate.

Symptoms and Related Conditions

• Many individuals are asymptomatic; others present mildly.

• Twenty-five percent of individuals do not present with complications.

• Deficiency in IgG2 or IgG4 may prompt testing for other disorders like systemic lupus erythematosus or rheumatoid arthritis.

Underlying Cause

• The underlying cause is unknown, but there are clues in genetic associations with T cell activation markers (HLA Doctor).

Common Variable Immunodeficiency (CVID)

Prevalence and Onset

• Relatively rare: 1 case in 25,000.

• Characterized by late-onset symptoms in the teens or twenties, triggered by infection or inflammation.

Underlying Traits and Mechanisms

• Underlying trait: low immunoglobulin count or hypogammaglobulinemia.

• Mechanism is harder to pinpoint than in X-linked agammaglobulinemia.

• 10% related to a genetic cause.

• Genes regulating T cell signaling in the ICOS cluster and the receptor CD19 (regulating B cell development and survival) are implicated.

• BAF and other immune signaling proteins cluster in the Tasi gene set, with mutations also found there.

• All these mutations affect the ability of B cells to mature and survive to make antibodies.

Environmental and Epigenetic Factors

• A case study in The Netherlands showed that even within the same family, environmental triggers and epigenetic factors could underlie CVID.

Symptoms and Management

• Symptoms include bronchitis, pneumonia, Giardia and campylobacter infection of the gut, and a contribution to cancer development.

• Managed by immunoglobulin transfusion, leading to reasonable survival rates.

T Cell Deficiencies

Impact and Treatment

• Each immunodeficiency is unique, and its impact can be mild to severe.

• The survival of the cell, how the cells communicate, and antibody production are impacted.

• Consequences of T cell defects can be radically different and more difficult to treat.

• Replacing immunoglobulins is easier because they can be synthesized.

T Cell Function and HIV

• T cells don't secrete anything like B cells and rely on communication with other parts of the immune system, especially cytotoxic CD8 T cells.

• Dysfunction of T cells in late-stage HIV disease can cause opportunistic pathogens to invade mucosal surfaces.
  

Advanced Treatments

These disorders require mutations from both parents, and manifestations can present quite early. Treatments for primary immunodeficiencies (particularly T cells) have become more advanced due to new technologies.

• CAR T cells and ablation of the immune system lead to the deletion of problematic parts of the immune system and the addition of more functional T cells.

Chronic Mucocutaneous Candidiasis

Genetic and Immune Aspects

• Inherited primary immunodeficiency due to a hereditary defect in the IL-17 pathway.

• IL-17 is a pro-inflammatory cytokine released by Th17 cells, induced by IL-23.

• Mutation in the STAT1 gene, critical for T cell differentiation, results in improper T cell development.

Symptoms and Related Infections

• Causes chronic infections with candida on the tongue, genital tract, skin, and fingernails

• HPV evades immune response by suppressing STAT1 signaling.

• Defect is known to show human papilloma virus infection.

• Onset can be seen quite early but does not appear to affect thriving capacity.

Severe Combined Immunodeficiency (SCID)

Prevalence and General Impact

• Affects 6-8 children in Australia and up to 70 children per year in the United States.

• Results from a combined B and T cell defect at different levels of lymphocyte maturation.

• Defects come from various sources.

Genetic and Enzyme Defects

• Most common autosomal recessive SCIDs affect the adenosine deaminase enzyme, which is critical to T cell survival.

• Screening looks for normal T cell function (T cell receptor excision circles).

Disease Progression and Common Causes

• If not treated promptly, the disease is normally fatal within the first two years of life.

• Opportunistic infections monopolize on the dysfunction of the T and B cells.

• The most common form results from a defect in the common gamma chain for multiple cytokine receptors, essential for B and T cell responses.

• Cytokine messages required for cell development and differentiation never arrive.

Receptor and Enzyme Defects

• SCID can also result from defects in the RAG1 and RAG2 enzymes, responsible for rearranging B and T cell receptors.

• These enzymes generate a wide diversity of receptors to recognize any pathogen.

• If antigen recognition receptors don't develop properly, the cells may be deleted.

Historical Treatment and Gene Therapy

• The little boy David Vetter was treated through residing in a sterile bubble but passed when a stem cell transplant infected cells with acquired Epstein Barr.

• Early gene therapies for SCID, based on the murine leukemia virus, have cured immunodeficiency disorder but can develop other secondary problems.

• Treatment from murine leukemia virus is a gamma retrovirus which insert an oncogene and cause cancer itself.

Modern Gene Therapy

• Gene therapies now turn to lentiviral-based vectors based on HIV one based protein, given that HIV can enter a resting immune cell and doesn't preferentially integrate into any particular kind of gene.

• Using HIV one based protein is seen as a step forward in addressing gene deficiencies.

Innate Immunodeficiencies

Overview

Chronic Granulomatous Disease

Prevalence and Pathophysiology

• Rare compared to SCID.

• Normal phagocytosis of pathogens is present, but there is a defect in NADPH oxidase, which is essential for killing bacteria or fungus.

Symptoms and Complications

• Patients are susceptible to bacterial infections like staphylococcus and aspergillus.

• Symptoms include abscesses in the lung, liver, spleen, bones, or skin.

• Complications can include bowel obstruction and urinary tract infection.

Treatment

• Treatment includes interferon to increase reactive oxygen species or bone marrow transplant.

Aicardi-Goutières Syndrome (AGS)

General Information

• Inherited disease resulting in neuroinflammation or encephalopathy of the central nervous system.

• White matter in the brain has a buildup of calcium inside.

• Presents severely from a few weeks after birth with neurological and organ abnormalities and the inability to thrive.

• No known cure.

Genetic and Protein Aspects

• Mutations occur in the SAMHD1 protein, which correlate with, but are not necessarily related to, calcium buildup.

• SAMHD1 is an immune response protein important for antiviral function, reducing deoxynucleotide triphosphates within the nucleus, restricting HIV.

Immune Dysregulation and Current Research

• In AGS, there is an inability to regulate type I interferons controlled by SAMHD1, causing calcium buildup.

• Current clinical trials are examining alternative methods such as repurposing drugs that target viral infection and targeting intracellular enzymatic pathways such as JAK1/2.

Conclusion

• Thank you for joining; feel free to reach out about any topics from the seminar.