[03.23b] Immunodeficiency, Transplant Rejection and Amyloidosis V2.1.pdf

Immunodeficiency, Transplant Rejection, and Amyloidosis

What is the subject of the lecture by J. Dy-Ledesma, MD, FPSP on 09/24/24?

Inherited genetic defects

What causes Primary Immunodeficiency?

Innate immunity or the humoral and/or cellular arms of adaptive immunity

What defense mechanisms are affected by Primary Immunodeficiency?

Infancy

When are most primary immunodeficiency diseases detected?

Susceptibility to recurrent infections

What is a clinical clue for primary immunodeficiency?

WBC functions or the complement system

What are typically affected by defects in innate immunity?

Increased susceptibility to infections

What is the end result of defects in innate immunity?

β2 chain of CD11/CD18 integrins

What is the defect in Leukocyte adhesion deficiency type 1?

Absence of Sialyl-Lewis X

What is the defect in Leukocyte adhesion deficiency type 2?

E- and P-selectins

What are Sialyl-Lewis X a fucose-containing ligand for?

WBCs cannot adhere to the endothelium, preventing migration to the tissues

What is the presentation of Leukocyte Adhesion Deficiency?

Mutation in LYST gene

What is the defect in Chédiak-Higashi syndrome?

Regulates lysosomal membrane traffic

What is the function of the LYST gene product?

Defective fusion of phagosomes and lysosomes

What is the result of the dysfunctional LYST protein in Chédiak-Higashi syndrome?

Defective phagocyte function

What is the ultimate result of the defective fusion of phagosomes and lysosomes in Chédiak-Higashi syndrome?

Leukocytes contain giant granules

What microscopic finding is readily appreciated in peripheral blood smears of Chédiak-Higashi syndrome patients?

Aberrant phagolysosome fusion

What causes the giant granules in leukocytes in Chédiak-Higashi syndrome?

Albinism and Bleeding disorders

What are two other abnormalities associated with Chédiak-Higashi syndrome?

Mutations in the CYPA, CYBB, or NCF1/2/4 gene

What is the defect in Chronic Granulomatous Disease (Bridges-Good syndrome)?

Phagocyte oxidase

What enzyme, generated by components encoded by defective genes, affects the bacterial killing process in Chronic Granulomatous Disease?

Generates superoxide

What is the function of phagocyte oxidase?

Macrophage-rich chronic inflammatory reaction

What presentation, which tries to control infections when initial neutrophil defense is inadequate, gives Chronic Granulomatous Disease its name?

Granulomas

What formation does Chronic Granulomatous Disease often lead to?

C2/C4 deficiency

What hereditary complement deficiency increases susceptibility to bacterial or viral infections?

C2 deficiency

What is the most common complement protein deficiency?

Increased bacterial or viral infections

What is the presentation of C2/C4 deficiency?

Susceptibility to serious and recurrent pyogenic infections

What is the presentation of C3 deficiency?

C5-9 deficiency

What hereditary complement deficiency increases susceptibility to recurrent Neisseria infections?

Required for the assembly of membrane attack complex (MAC)

Why are terminal complement components C5-9 important?

Severe Combined Immunodeficiency (SCID)

What group of genetically distinct syndromes involves defective cell-mediated (T-cell) and humoral (B-cell) responses?

Oral candidiasis, extensive diaper rash, and a general failure to thrive

What is the presentation of SCID in infants?

Candida albicans, P. jirovecii, Pseudomonas, Cytomegalovirus, Varicella, Bacteria

What wide range of pathogens cause infections encountered in SCID?

Bone marrow transplant

What is the treatment for SCID, without which death occurs within the first year of life?

Thymus with lobules of undifferentiated epithelial cells resembling fetal thymus

What are the microscopic findings in X-linked SCID?

Thymus containing remnants of Hassall’s corpuscles

What are the microscopic findings in ADA deficient SCID?

Other lymphoid tissues are hypoplastic

What is a finding common to both X-linked and ADA-deficient SCID?

X-linked SCID

What is the most common form of SCID?

Mutation in the common $\gamma$-chain subunit of a cytokine receptor

What is the defect in X-linked SCID?

Transmembrane protein

What component is lost in X-linked SCID that is the signal-transducing component of receptors for certain interleukins essential for T-cell precursor survival and proliferation?

Defect in the earliest stages of T-cell development

What is the result of the mutation in the common $\gamma$-chain subunit in X-linked SCID?

Deficiency of the enzyme Adenosine deaminase (ADA)

What defective gene product is implicated in Autosomal Recessive SCID?

Accumulation of deoxyadenosine and its derivatives

What does ADA deficiency lead to?

Toxic to rapidly dividing immature T-lymphocytes

What effect does the accumulation of deoxyadenosine have in Autosomal Recessive SCID?

Bruton’s Agammaglobulinemia

What is another name for X-linked Agammaglobulinemia (XLA)?

No immunoglobulin or antibody production

What does Agammaglobulinemia mean?

Failure of B-cell precursors to develop into mature B-cells (plasma cells)

What is the defect in XLA?

Only plasma cells

What cells can secrete antibodies?

Recurrent bacterial infections of the respiratory tract

What is the presentation of XLA in most cases?

6 months of age

When is the onset of XLA symptoms?

Maternal immunoglobulins are depleted

Why does XLA onset occur around 6 months of age?

H. influenzae, S. pneumoniae, S. aureus, Enterovirus, G. lamblia

What are frequent causative agents in XLA?

G. lamblia

What intestinal protozoan causes persistent infections in persons with XLA, normally resisted by secreted IgA?

Normally opsonized by antibodies and cleared by phagocytosis

What is the commonality among the causative agents in XLA?

T-cell mediated immunity

What part of the adaptive immune system is intact and handles most fungal, protozoal, and intracellular viral infections well in XLA?

IV Ig therapy

What is the treatment for XLA?

Decreased B-cells and immunoglobulins, underdeveloped germinal centers of lymph nodes, Peyer’s patches, appendix, and tonsils, and absent plasma cells throughout the body

What are the histologic findings in XLA?

Bruton tyrosine kinase (BTK) gene

What gene, encoded on the long arm of the X chromosome, is mutated in XLA?

B-cell maturation is arrested

What happens when the BTK gene is mutated?

22q11 deletion syndrome

What is the defect in DiGeorge Syndrome?

Thymic hypoplasia or lack of thymus

What causes T-cell deficiency and variable absence of cell-mediated immunity in DiGeorge Syndrome?

Failure of the development of the 3rd and 4th pharyngeal pouches

What causes the thymic and other organ defects in DiGeorge Syndrome?

Thymus, parathyroid, c-cells of thyroid, and ultimobranchial body

What structures arise from the 3rd and 4th pharyngeal pouches?

Tetany

What symptom results from the lack of parathyroid in DiGeorge Syndrome?

Low numbers of T-lymphocytes in the blood and lymphoid tissues

What results in poor defense against certain fungal and viral infections in DiGeorge Syndrome?

Hypogammaglobulinemia

What is the common feature of the heterogenous group of disorders called Common Variable Immunodeficiency (CVID)?

B-cells are unable to differentiate or mature into plasma cells, high frequency of autoimmune disease, increased risk for lymphoid malignancy and gastric cancer

What are three similarities between CVID and XLA/Bruton’s agammaglobulinemia?

Most individuals with CVID have near normal or normal number of B-cells in the blood and lymphoid tissues

What is a difference between CVID and XLA regarding B-cell numbers?

Childhood/late adolescence (later in life)

When do CVID symptoms typically onset?

B-cell activating factor (BAFF) and Inducible co-stimulator (ICOS)

What are two receptors associated with underlying abnormality in some familial types of CVID?

Recurrent sinopulmonary pyogenic infections

What is a presentation of CVID?

Germinal centers in lymphoid tissues are hyperplastic

What is a histologic finding in CVID?

Normal or elevated IgM levels but deficient in IgA, IgG, and IgE

What characterizes Hyper IgM syndrome?

CD40 ligand (CD40L) and activation-induced cytidine deaminase (AID) enzyme mutation

What are two defects associated with Hyper IgM syndrome?

Induces immunoglobulin class switching and affinity maturation in B cells

What does the interaction between CD40L on T-cells and CD40 on B-cells, macrophages, and dendritic cells do?

Recurrent pyogenic infections

What is a presentation of Hyper IgM syndrome due to low opsonizing IgG antibodies and impaired affinity maturation?

Susceptibility to P. jirovecii pneumonia

What is a specific susceptibility in Hyper IgM syndrome due to defective CD40 ligand-mediated macrophage activation?

Impaired differentiation of naive B-lymphocytes to IgA-producing plasma cells

What is the defect in Isolated IgA Deficiency?

Extremely low levels of both serum and secretory IgA

What do affected individuals with Isolated IgA Deficiency have?

Most individuals with IgA deficiency are asymptomatic

Why are IgA deficient individuals often asymptomatic despite IgA being the major antibody in mucosal secretions?

Recurrent sinopulmonary infections, diarrhea, high frequency of allergies, and variety of autoimmune diseases (Systemic lupus erythematosus, Rheumatoid arthritis)

What are presentations in symptomatic IgA deficiency patients?

Anaphylactic reactions

What can occur in some IgA deficient patients when transfused with blood containing normal IgA?

Inability to eliminate Epstein-Barr Virus (EBV)

What characterizes X-Linked Lymphoproliferative Syndrome?

Fulminant infectious mononucleosis and the development of B-cell tumors

What does the failure to eliminate EBV eventually lead to in X-Linked Lymphoproliferative Syndrome?

Mutations in the gene encoding an adapter molecule called SLAM-associated protein

What is the defect in X-Linked Lymphoproliferative Syndrome?

Attenuates Natural Killer and T-cell activation

What does the SLAM-associated protein mutation do?

Wiskott-Aldrich Syndrome and Ataxia Telangiectasia

What two inherited systemic disorders have immunodeficiency as the main clinical manifestation?

X-linked, recessive

What is the inheritance pattern of Wiskott-Aldrich Syndrome?

Mutations in gene that encodes for Wiskott-Aldrich Syndrome Proteins (WASP)

What is the defect in Wiskott-Aldrich Syndrome?

Progressive depletion of T-cells

What is the result of mutations in the WASP gene?

Thrombocytopenia, Eczema, and Marked vulnerability to recurrent infection

What are three classic presentations of Wiskott-Aldrich Syndrome?

Do not make antibodies to polysaccharide antigens and response to protein antigen is poor

What is the pathology regarding antibody response in Wiskott-Aldrich Syndrome?

Low IgM, normal IgG, and elevated IgA and IgE levels

What are the abnormal Ig levels in Wiskott-Aldrich Syndrome?

Non-Hodgkin’s B-cell Lymphoma

What type of tumor are patients with Wiskott-Aldrich Syndrome prone to developing?

Hematopoietic Stem Cell (HSC) Transplant or Bone marrow transplant

What is the treatment for Wiskott-Aldrich Syndrome?

Autosomal recessive disorder

What is the inheritance pattern of Ataxia Telangiectasia?

Mutation in gene that codes for a protein kinase called Ataxia Telangiectasia Mutated (ATM)

What is the defect in Ataxia Telangiectasia?

Abnormalities in DNA repair

What is the result of the deficiency in ATM protein?

Impair the generation of antigen receptors

What may abnormalities in DNA repair in Ataxia Telangiectasia impair?

Defective IgA and IgG2

What are the most prominent humoral immune abnormalities in Ataxia Telangiectasia?

Abnormal gait, Vascular malformations, Neurologic deficits, and Increased incidence of tumors (lymphoma)

What are four presentations of Ataxia Telangiectasia?