Immunodeficiencies Quiz

Immunology II - BMS44210A

• Course offered at Abu Dhabi University
• Instructor: Dr. Afsheen Raza
• Email: [email protected]
• Fall Semester 2024-2025

Immunodeficiencies and Autoimmunity (CLO4)

• Learning Objectives:
  • Primary immunodeficiencies of lymphoid lineage
  • B-cell, T-cell, and combined T and B-cell immunodeficiency disorders
  • Primary immunodeficiencies of the myeloid lineage
  • Testing for primary immunodeficiencies
  • Treatment of primary immunodeficiencies

Immunodeficiencies and Autoimmunity

• Immune system failure can have unintended consequences
• Autoimmunity occurs when the immune system misidentifies self and attacks host cells/tissues.
• Immunodeficiency results from the immune system failing to protect the host from pathogens or malignancies.

Immunodeficiencies

• Primary immunodeficiency is a genetic or developmental defect within the immune system, present at birth.
• Symptoms might not manifest until later in life.
• Secondary immunodeficiency (acquired) is the loss of immune function due to exposure to various agents.
  • Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus 1 (HIV-1) infection.

Primary Immunodeficiencies

• Can affect either adaptive or innate immune functions.
• Adaptive immunodeficiencies involve components of adaptive immunity such as T and B cells.
• Innate immunodeficiencies impair components of the innate system such as phagocytes or complements.
• Most immunodeficiency-causing defects affect lymphoid and myeloid cells.
  • Lymphoid disorders impact T, B, or both cells.
  • Myeloid disorders affect cells with phagocytic function.

Recall - Lymphoid or Myeloid Lineages

• Visualizes the development of lymphoid and myeloid lineages.
• Lymphoid progenitor cells give rise to all lymphoid cells.
• Myeloid progenitor cells give rise to all myeloid cells.
• Dendritic cells can originate from either lineage.

Primary Immunodeficiencies

• Most are inherited
• Genetic defects leading to these deficiencies have been determined.
• Some immunodeficiencies stem from developmental defects during embryogenesis and impair proper function of immune organs.

Types of Primary Immunodeficiencies

• Diagram illustrating various types of primary immunodeficiencies, categorized by affected immune components (phagocytic, humoral, cell-mediated, combined).

Primary Immunodeficiencies

• Defects' impact depends on the number and types of immune system components involved.
• Early hematopoietic defects affect the entire immune system.
• Reticular dysgenesis: a stem-cell defect impacting the development of all leukocytes leads to vulnerability to various infections.
• Defective phagocytic function results in bacterial susceptibility.
• More specific, less severe consequences result from defects in later-differentiated immune system components.

Primary Lymphoid Immunodeficiencies (B-cell deficiency disorders)

• Characterized by complete or selective absence of mature recirculating, B cells, plasma cells and immunoglobulins.

B-cell immunodeficiency Disorders

• Often involve recurrent bacterial infections, but viral and fungal infections are unaffected.
• Common causes: infections by encapsulated bacteria (staphylococci, streptococci, and pneumococci) needing antibodies for opsonization and clearance.

X-Linked Agammaglobulinemia (XLA)

• B-cell defect characterized by extremely low IgG levels and absence of other immunoglobulin classes.
• Defect in B-cell signaling, due to a defect in Bruton's tyrosine kinase (Btk) protein.
• Mutations in the BTK gene prevent BTK protein production and block B-cell development.
• Defective B cells remain in pre-B or immature stages, leading to lacking antibodies.
• Inherited in an X-linked recessive pattern, affecting primarily males.

T-cell Immunodeficiency Disorders

• A T-cell deficiency affects humoral and cell-mediated responses.
• Significant impact on cell-mediated immunity, causing a reduction in delayed-type hypersensitivity responses and cell-mediated cytotoxicity.
• Intracellular pathogens (Candida albicans, Pneumocystis carinii, Mycobacteria) vulnerability is common.
• Infections with viruses (cytomegalovirus, attenuated measles vaccine) can be life-threatening.
• Reduced antibody production after immunization.

Immune Disorders Involving the Thymus

• Several immunodeficiency syndromes related to thymus failure to develop.
• DiGeorge syndrome (congenital thymic aplasia) has a characteristic association with a deletion in chromosome 22 (22q11.2).
• Absence of the thymus, affecting T-cell function (helper, cytolytic, regulatory cells).
• Compromised immunity to viruses and fungi.
• Potential thymus transplantation to correct the defect, but heart disease can impede long-term survival.

Combined T and B-cell immunodeficiency Disorders

• Combined deficiencies of humoral and cell-mediated branches are the most severe immunodeficiency disorders.
• Onset of infections is early in infancy, and prognosis is poor without intervention to reconstitute the immune system; a high mortality rate is associated with these conditions.
• SCID (Severe Combined Immunodeficiency) involves defects in lymphoid development (T and B cells).
• Generally, very low circulating lymphocytes.
• Immunodeficiency leads to an incapacity to mount T-mediated immune responses; thymus development is often defective, and the few circulating T cells do not respond to stimulation.

Combined T and B-cell immunodeficiency disorders (SCID)

• SCID results in severe recurrent infections.
• SCID (Severe Combined Immunodeficiency) is often fatal in early years.
• Many agents like fungi or viruses, typically handled by T-cell immunity, impact infants.
• Maternal antibodies initially protect infants; these antibodies eventually deplete, leading to frequent infections.

Causes of Severe Combined Immunodeficiency (SCID)

• Often due to defects in genes essential for immune function, such as RAG genes, and cytokine receptors (IL-2, IL-4, IL-7, ...).
• Expression of class II MHC molecules, as well as CD40 Ligand, affect B-lymphocyte development.

Immunodeficiencies of the Myeloid Lineage

• Defects in myeloid cell lineage impact innate immune functions.
• Most myeloid defects lead to impaired phagocytic processes, causing recurrent microbial infections.
• Several steps in phagocytic processes can lead to immunodeficiency.
  • Cell motility, adherence, phagocytosis, and killing by macrophages.

Quantitative deficiencies in neutrophils

• Neutrophils deficiency (agranulocytosis or neutropenia) can range from near absence of cells to reduced counts.

Congenital neutropenia

• Caused by genetic defects impacting myeloid progenitor stem cells.
• Reduced neutrophil production.
• May sometimes be an autosomal dominant condition.

Immunodeficiency of the Myeloid Lineage - Screening and Treatment

• Testing involves complete blood counts (WBC), differentials, and x-rays (thymic shadow).

• SCID diagnosis confirms very low/absent T-cells and impaired T-cell function.

• T-cell receptor excision circles (TREC) deficiencies can be determined using PCR tests.

• Treatment for antibody production disorders involve immunoglobulin replacement (pooled human gamma globulin).

• Treatment options in general:

  • Replacing missing proteins
  • Replacing missing cells/lineages
  • Correcting faulty genes

• Bone marrow transplatation is a possible treatment, as well are other newer therapeutic options.

General Notes

• Several diagrams show the stages of lymphocyte development and the defects associated with immunodeficiency disorders.
• Information about the inheritance patterns and frequency of different types of immunodeficiency disorders is provided.

Test your knowledge on myeloid lineage immunodeficiencies and Severe Combined Immunodeficiency (SCID). This quiz covers key concepts, consequences of defects, and clinical implications related to these conditions. Challenge yourself with questions about genetic factors and infection susceptibility.