inc Ch 26: Toxic Granulation, WBC Anomalies, Leukemic Cells

INBORN ERRORS OF IMMUNITY

IEI meaning

Severe Combined Immune Deficiency

includes a group of IEIs associated with defects in both cellular and humoralimmunity.

• Nearly all patients with SCID experience a marked

decrease in circulating T cells, poorly functioning B cells,

hypogammaglobulinemia, and symptoms during infancy

First 2 years

if left untreated, most patients with SCID die within _ in life from overwhelming bacterial, viral, and/or fungal infections

Hematopoietic Stem Cell Therapy/HSCT, Gene therapy

Potential curative options are ?

Common Gamma Chain Deficiency/X-linked SCID/T-B+ SCID

• most common SCID

• initiates from a mutation in IL2RG located at Xq13.1

• Infants With this disease have no thymus, tonsils, or lymph nodes and experience severe life-threatening infections

IL2RG

• normally encodes the gamma chain protein within receptor complexes that bind interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21

• mutation in this gene leads to truncated gamma chain proteins and faulty signal transduction that impairs T and NK cell development.

WBC, T & NK lymphocytes

in affected infants is decreased as a result of severely decreased and _. _ are generally adequate in number but are dysfunctional without T cell signaling

Adenosine deaminase deficiency (ADA-SCID)

T–B– SCID1 and represents 10% to 20% of SCID cases. It is an

autosomal recessive disorder caused by a mutation in the ADA

gene located at chromosome 20q13.12

• there is intracellular and extracellular accumulation of toxic levels of adenosine and deoxyadenosine in lymphocytes, causing profound decreases in T , B, and NK cells

• Symptoms: severe recurring, life-threatening bacterial, viral, and fungal infections beginning early in life. + skeletal abnormalities, neurologic deficits,and skin rashes

Adenosine deaminase

is a key component in the metabolic breakdown of adenosine

triphosphate (ATP) and RNA in all cells

Wiskott-Aldrich Syndrome

classified as a combined immunodeficiency with associated or syndromic features.

• rare X-linked disease caused by one of more than 450 mutations in that gene

Wiskott-Aldrich syndrome protein (WASP)

controls RNA polymerase II–dependent transcription and has a critical role in actin cytoskeleton remodeling of hematopoietic cells

• low amount if this an impact on the stability of the immunologic synapse, the site where T-cells and antigen-presenting cells interact

Gene therapy

promising approach most appropriate for patients with W AS who lack a matched donor

Hematopoietic Stem Cell Therapy

can be curative in patients with human leukocyte antigen (HLA)- matched donors

22q11.2 deletion syndrome/DiGeorge syndrome

a heterozygous microdeletion of 1.5 to 3 million base pairs on chromosome 22 at q11.2 resulting in a loss of over 100 genes and their encoded protein products

• deletion breakpoint and genes lost in the deletion can differ among patients, contributing to the variable clinical phenotype.

Haploinsufficiency

caused by the loss of T-box transcription factor 1 gene (TBX1), DiGeorge Syndrome Critical Region 8 (DGCR8), and several microRNAs result in congenital malformations and other clinical manifestations in 22DS

Peroxidase-positive

Abnormal granules in phagocytes

Peroxidase-negative

Abnormal granules in lymphocytes

Chediak-Higashi Syndrome

Leukocyte Adhesion Disorder (LAD)

Characterized by the presence of giant fused cytoplasmic granules/inclusions in leukocytes (granulocytes, monocytes,

and lymphocytes (NK and cytotoxic T cells)

Manifestations:

• partial albinism (due to abnormal packaging of melanosomes)

• severe recurrent bacterial infections

• mild bleeding

• Easy bruising

• Progressive neurological impairment

Neutrophil, Chediak-Higashi syndrome

Identify the cell and abnormality

Basophil, Chediak-Higashi Syndrome

Identify cell and abnormality

Eosinophil, Chediak Higashi Syndrome

Identify cell and abnormality

Leukocyte Adhesion Disorder/LAD

● Inability of neutrophils and monocytes to move from the peripheral circulation to sites of infections

● Manifestations:

○ recurrent infection

○ impaired wound healing

○ developmental abnormalities

○ increased bleeding risk

Leukocyte Adhesion Disorder Type 1

• most common type

• Nonneuropathic (-) cns disease

• Neutrophils accumulate in peripheral circulation but cannot reach sites of infection in tissues due to adhesion problem

• Life span: 6-80+yrs

Leukocyte Adhesion Disorder Type II

Decrease leukocyte adhesion to the vascular endothelium and impairs transmigration to sites of infection

• From infancy

• No skeletal abnormalities

• acute neuropathic

• Life span: <2yrs

• Panerhnic

Leukocyte Adhesion Disorder Type III

Normal integrin expression but fail to respond to external

signals

• subacute neuropathic

• 2-60yrs

Chronic Granulomatous Disease

Characterized by decreased ability of neutrophils, monocytes, macrophages, and eosinophils to kill phagocytized

bacteria and yeast

● Manifestations:

○ catalase-positive bacterial and fungal infections

○ colitis and granuloma formation in the GIT and GUT

● Screening test: dihydrorhodamine 123 or nitroblue tetrazolium test (NBTZ)

○ Positive: bite color (normal phagocyte function)

○ Negative: colorless (CGD)

● Confirmatory test: DNA sequencing

NADPH oxidase deficiency

Defect in the respiratory burst and production of antimicrobial superoxide anions and other reactive oxygen species

(H203, hypochlorous acid, etc.) = ?

dihydrorhodamine 123, nitroblue tetrazolium test

Screening tests for CGD

Myeloperoxidase Deficiency

● Most common inherited disorder of phagocytes

● Decreased MPO production

● Most individuals are asymptomatic

● Neutrophils has a normal morphology

Gaucher Disease

● Most common lysosomal storage disorder

● Defect or deficiency in the catabolic enzyme

B-glucocerebrosidase (necessary for glycolipid

metabolism)

● Unmetabolized substrate sphingolipid

glucocerebrosidase accumulates in the lysosomes

of macrophages throughout the body, including

microglia (CNS) and osteoclast (bone)

● Found in:

○ Spleen

○ Liver

○ Bone marrow

● Lysosome-engorged macrophages with eccentric

nucleus

● Fibrillar blue-gray cytoplasm with a striated or

wrinkled appearance (onion skin-like or

crumpled tissue paper)

● Stain positive with:

○ PAS

○ ACP

○ trichrome

○ aldehyde fuchsin

Pseudo-Gaucher cells

● Seen in patients with thalassemia, myeloid neoplasm,

ALL, non-Hodgkin lymphoma, and plasma cell neoplasm

● Seen on cancer patients

● Composition: needle-like inclusion

Niemann-Pick Disease

● Deficiency of lysosomal hydrolase enzyme acid

sphingomyelinase (ASM)

● Characterized by an accumulation of fat

(sphingomyelin) in cellular lysosomes of liver,

spleen, and lungs

Foam cells

Macrophages with cytoplasm packed with lipid-filled lysosomes that appear as small vacuoles (foam)

Sea-blue histiocytes

Macrophage filled with ceroid (of its cytoplasm) that appears blue on Romanowsky-type stain

Bruton Tyrosine Kinase Deficiency

caused by a mutation in the gene encoding BTK (Xq21.3-Xq22)

• leads leads to marked reduction in B cells, Absent tonsils and adenoids, inability to produce plasma cells

• Clinical manifestation after 3-18 weeks

• Recurrent otitis, conjunctivitis, diarrhea, sinus, and skin infections

Chromosome 1q42.3

Caused by a mutation in lysosomal trafficking regulator (LYST) gene