Primary Immunodeficiency Diseases (PIDs): Microbiology & Immunology Study Notes

Primary Immunodeficiency Diseases (PIDs)

Introduction to PIDs

Primary immunodeficiency diseases (PIDs) are a group of disorders caused by intrinsic, usually inherited, defects in the immune system. These conditions result in increased susceptibility to infections and may be associated with autoimmune diseases. PIDs are distinct from secondary (acquired) immunodeficiencies, which result from external factors such as malnutrition, malignancy, drugs, or infections like HIV.

• Primary immune deficiency (PID): Inherited defects, often genetic.

• Secondary immune deficiency: Acquired due to malnutrition, disease, malignancy, drugs, or HIV/AIDS.

Classification of PIDs

PIDs are classified based on the affected component of the immune system. Understanding these categories helps in diagnosis and management.

• Combined immunodeficiencies: Affect both T and B cells (e.g., X-linked SCID, ADA deficiency).

• Well-defined syndromes with immunodeficiency: Syndromes like Wiskott-Aldrich syndrome.

• Predominantly antibody deficiencies: CVID, selective IgA deficiency.

• Diseases of immune dysregulation: Chediak-Higashi syndrome, XLP.

• Congenital defects of phagocyte number/function: Chronic granulomatous disorder.

• Defects in innate immunity: NEMO deficiency.

• Autoinflammatory disorders: Blau syndrome.

• Complement deficiencies: Affect complement proteins.

Genetics of PIDs

PIDs are a heterogeneous group of rare diseases, often inherited as X-linked or autosomal recessive/dominant disorders. Occasionally, mutations arise de novo. Genetic defects can lead to missing enzymes, developmental arrest, non-functional proteins, abnormal DNA repair, altered signal transduction, and impaired cellular communication.

• Examples: ADA deficiency, IL2RG mutations, RAG1/RAG2 mutations.

Diagnosis of Immune Deficiencies

Diagnosis involves clinical history, genetic testing, and functional assays of immune components.

• Recurrent opportunistic infections are a key indicator.

• Genetic testing (whole genome or exome sequencing).

• Assessment of immunoglobulin, complement, neutrophil/phagocyte, and cell-mediated immune function.

Signs of a PID

• Recurrent infections (e.g., >8 RTIs/year in children, >4 in adults).

• Opportunistic infections, infections at unusual sites.

• Chronic, unresponsive infections.

• Early organ damage (e.g., bronchiectasis).

• Family history of immune deficiency.

Shared Patterns of Infections and PIDs

Different types of PIDs predispose to specific patterns of infections.

	Phagocyte deficiency	Complement deficiency	T lymphocyte deficiency	Antibody deficiency
Bacteria	Staphylococcus aureus, Pseudomonas, Burkholderia, Mycobacteria	Neisseria meningitidis, Streptococcus pneumoniae	Mycobacterium tuberculosis, Atypical mycobacteria	Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus
Fungi	Candida spp., Aspergillus spp.		Candida spp., Aspergillus spp., Pneumocystis jirovecii
Viruses			CMV, EBV, Herpes zoster
Protozoa			Toxoplasma gondii	Giardia lamblia

Important Steps in Lymphocyte Development

Lymphocyte development involves several checkpoints and gene rearrangements. Defects in these steps can result in immunodeficiency.

• VDJ recombination: RAG1, RAG2, ARTEMIS genes.

• Checkpoint proteins: BTK, CD3, ZAP70, TAP2.

• Key enzymes: ADA, JAK3, PNP.

Genetic Defects Responsible for SCID

Severe Combined Immunodeficiency (SCID) is caused by mutations in various genes, including IL2RG, ADA, JAK3, RAG1/RAG2, and others. These mutations disrupt lymphocyte development and function.

Absolute Lymphocyte Counts in Infants with SCID

Infants with SCID have significantly reduced lymphocyte counts compared to normal ranges, reflecting impaired immune development.

X-linked SCID (X-SCID)

X-SCID is a severe PID occurring exclusively in males, characterized by very few T or NK cells and defective B cells. It is caused by mutations in the IL2RG gene on the X chromosome, affecting the common gamma chain essential for lymphocyte maturation.

• Symptoms: Persistent infections, failure to thrive, chronic diarrhea, skin rashes.

• Prognosis: Poor life expectancy without treatment.

Treatment for SCID

• Hematopoietic stem cell transplantation (HSCT): Matched or haploidentical donors, cord blood, in utero transplants.

• Gene therapy: Retroviral vectors to introduce functional genes; newer vectors are safer.

T Lymphocyte Functions & Dysfunctions

T lymphocytes are essential for adaptive immunity. Dysfunction can result from failure of thymic development, cytokine production, or apoptosis regulation, leading to combined immunodeficiencies.

T Cell Deficiencies

T cell deficiencies are characterized by increased susceptibility to infections, especially by viruses, fungi, and intracellular bacteria. Examples include DiGeorge syndrome and CD40L deficiency.

CD40 Ligand Deficiency (X-linked Hyper-IgM Syndrome)

CD40L deficiency is a severe PID caused by mutations in the CD40L gene, affecting co-stimulation between B and T cells. This impairs immunoglobulin isotype switching and germinal center formation.

• Clinical features: Increased IgM, decreased IgA, IgG, IgE.

• Symptoms: Severe infections, pneumonia, sinusitis, otitis, chronic diarrhea.

• Treatment: Immunoglobulin replacement, antibiotics, HSCT.

Antibody Deficiencies

Antibody deficiencies lead to recurrent bacterial infections, especially of the respiratory and GI tract. The most common PID is selective IgA deficiency.

• Selective IgA deficiency: Low/undetectable IgA, often asymptomatic, but 30% have mild infections.

• Common variable immune deficiency (CVID): Low IgG, poor antibody response, associated with autoimmune diseases.

Immunoglobulin Classes and Their Functions

Isotype	Serum concentration (g/L)	Binding sites	Main functions	Complement fixation	Placental passage	Reacts with FcR
IgG	5-12	2	Neutralization, opsonization	++	+	L, M, N, P, E
IgM	0.5-1.8	10	Opsonization	+++	-	L, M, N, P
IgA	0.8-4.0	2	Neutralization at mucosal surfaces	+	-	L, M, N, P
IgE	0.00002	2	Immunity to parasites, allergy	-	-	B, E
IgD	0.03	2	Lymphocyte membrane receptor	-	-	L

Syndromic Immunodeficiencies: Wiskott-Aldrich Syndrome (WAS)

WAS is a complex PID with variable phenotypes, classically presenting with a triad of bleeding tendency (thrombocytopenia), recurrent infections, and eczema. Patients are at increased risk for autoimmune diseases and malignancies.

• Gene mapped to Xp11.22; WAS protein controls actin filament assembly.

• Mutations affect lymphocyte and megakaryocyte function.

Role of the Actin Cytoskeleton in T-cell Function

The actin cytoskeleton is essential for T cell movement, division, and immune synapse formation. WAS protein regulates actin filament assembly, and mutations disrupt immune cell function.

Complement Deficiency

Deficiencies in complement proteins impair immune activation, while defects in complement inhibitors can lead to overactive responses. Complement deficiencies predispose to infections by encapsulated bacteria.

Phagocytic Deficiencies

Phagocytic deficiencies, such as chronic granulomatous disease, result from defects in enzymes like NADPH oxidase, leading to impaired killing of catalase-positive bacteria and increased susceptibility to infections.

Therapeutic Options for PIDs

• Prevent infection: Prophylactic antibiotics.

• Passive immunotherapy: Immunoglobulin replacement.

• Replace faulty cells: Bone marrow or stem cell transplantation.

• Gene therapy: For select conditions where transplantation is not feasible.

Summary

PIDs are hereditary immune deficiencies with diverse genetic causes and clinical presentations. Key examples include X-linked SCID, Hyper IgM syndrome, Wiskott-Aldrich syndrome, phagocytic and complement deficiencies. Diagnosis relies on clinical, genetic, and laboratory assessment, and treatment options include immunoglobulin replacement, antibiotics, transplantation, and gene therapy.