Immunodeficiencies

Question 1

DiGeorge Syndromes

Answer 1

T cell deficiency (lack of T cells)

Parathyroid , thymic, hypoplasia and malformation of outflow vessels of the heart, facial abnormalities, recurrent infections

Key feature is HYPOCALCEMIA

Tetany, seizures in infants

22q11 chromosome deletion

Question 2

WHN

Answer 2

Congenital alopecia and nail dystrophy

Question 3

CD3 Deficiency

Answer 3

Autoimmune hemolytic anemia and severe infections, recurrent hemophilus influenza pneumonia and otitis media

Question 4

MHC I Deficiency

Answer 4

Decreased number of CD8+

Inability of Tap1 to transfer peptides to the ER

Recurring VIRAL infections

Normal CD4+, Ab production and DTH

Question 5

MHC II Deficiency (Bare Lymphocyte Syndrome)

Answer 5

Persistent diarrhea, bacterial pneumonia, viral and candidal infections, low CD4+ cells/no MHC II on pro APCs

Genes for MHC II on Chrom. 6 intact

Variable hypogammaglobulinemia (IgA and IgG2)

Mutations in genes encoding for transcription factors that regulate expression of MHCII genes

Question 6

LCK Deficiency

Answer 6

Bacterial, viral, fungal infections, lymphopenia and hypogammaglobulinaemia

Question 7

ZAP70 Deficiency

Answer 7

Decreased CD4/CD8+ and severe recurrent infections

Question 8

CD8 Deficiency

Answer 8

No CD8+, recurrent respiratory infections

Question 9

HIGM1

Answer 9

Pneumonia, pyogenic infections, bacterial infections

Normal response to encapsulated infections

High IgM, low or absence of serum IgG, IgA, IgE

Impaired class switching, somatic hypermutation

Normal peripheral B cells, LOW MEMORY CELLS

X-linked CD40L (2/3 of cases, male only), autosomal CD40 Deficiency (M & F, 1/3 of cases)

Question 10

Common Gamma Chain Deficiency (yc or IL-2Ry)

Answer 10

Most common SCID

X-linked recessive, only males

T-, B+, NK-

No functional B cells since T cells unable to help

Fungal infections, chronic diarrhea, skin, mouth and throat lesions

Question 11

Jak 3 Deficiency

Answer 11

T-, B+, NK-

Autosomal Recessive

Defect in IL-2 receptor signaling

Fungal infections, chronic diarrhea, skin, mouth and throat lesions

Question 12

Wiskott-Aldrich Syndrome

Answer 12

X-links recessive, progressive decrease in T cells

Defect in WASP - cytoskeleton protein

Only expressed on hematopoietic lineage

Low IgM, Normal IgG, elevate IgA/IgE

Thrombocytopenia, small platelets/dysfunction, Eczema, recurrent infections from encapsulated bacteria, (infants have longer bleeding after circumcision, bloody diarrhea, bruising)

Question 13

IPEX (Immunodysregulation, Polyendocrinopathy and Enteropathy)

Answer 13

X-linked defect in T cell function after maturation

Self reactive T Effector Cells are not inhibited

Mutations in FOXP3

Loss of CD4/CD25 Treg cells

Question 14

ALPS (Autoimmune Lymphoproliferative Syndrome)

Answer 14

Defects in Fas/FasL, Caspase 8, 10 genes

Abrogate Formation of death inducing signaling complex (DISC)

Interferes with apoptosis of T effector cells

Question 15

X Linked Briton Agammaglobulinemia (affects males only)

Answer 15

Low/absent IgG, IgA, IgM

Mutation in BTK gene

Diagnosis 5-6 months old

Defect in rearrangement of Ig heavy chain genes

Early B cell development arrested at Pre-B cell stage (never mature)

NO PLASMA CELLS

Secondary Lymph organs poorly developed

Severe bacterial infections

Question 16

Autosomal Recessive Agammaglobulinemia (affects males and females)

Answer 16

Low/absent IgG, IgA, IgM

Mutations in u, Igalpha, delta5, BLNK

BLNK: amplifies signal transduction
Delta 5: encodes surrogate light chain

Pre B cells do not mature

Question 17

Common Variable Immune Deficiencies

Answer 17

Associated with hypogammaglobulinemia

Low IgG, IgA

Normal/low IgM

Males and females equally affected

Diagnosed at 2 years, Onset after 4-5 years

Some have low B cells, defects in their formation or Abs against B cells (inherited vs. acquired)

Recurrent bacterial infections

Question 18

IgA Deficiency

Answer 18

Low IgA, normal IgG/IgM

Prevalence may be higher in male

Disorder of maturation or terminal differentiation of secreting B cells

Prone to infections in GI tract in epithelial areas, mom with this will have child with higher rate of disease

Question 19

Isolated IgG Subclass Deficiency

Answer 19

Decreased concentrations of one or more IgG subclass

Total IgG, IgM, IgA, IgE are normal

Low IgG2 frequent in children (poor response to polysaccharide Ags)

IgG4 levels vary widely

Recurrent viral/bacterial infection in respiratory tract

Question 20

Transient Hypogammaglobulinemia of Infancy

Answer 20

Low IgA/IgG

Normal IgM

Intrinsic Ig production delayed up to 36 months

Increased sinopulmonary infections

Ig concentrations normalize by 2-4 years

Question 21

Severe Chronic Neutropenia

Answer 21

Defect in life cycle and anatomy of neutrophils

Decreased absolute neutrophil count (<500 cells/mm^3)

Suppressed inflammation

Increased susceptibility to severe bacterial and fungal infections

Question 22

Chronic Granulomatous Disease (CGD)

Answer 22

Tendency to form granulomas

Most frequent phagocytic primary immunodeficiency

More common in males

NADPH oxidase Deficiency, failure to generate superoxide anion and O2 radicals

Defective elimination of extracellular pathogens i.e. bacteria and fungi

Recurrent infection with catalase positive organisms

Question 23

Myeloperoxidase Deficiency (MPO)

Answer 23

Autosomal recessive

Most common phagocyte DISORDER

Diagnosis by staining neutrophils for MPO activity

Almost exclusively seen in setting of diabetes

Neutrophils cant kill Candida in vitro

Question 24

Defect in the IFN-y-IL-12 Axis

Answer 24

POSITIVE REGULATORY LOOP

Normally, IL-12 from macrophage binds IL-12R, stimulates IFN-y release by T cells and NK Cells

Macrophage binds IFN-yR, produces H2O2 and TNF-alpha and IL-12

Increased susceptibility to nontuberculous mycobacteria from mutations in: IFN-y RC, IL-12 Rc, p40 subunit of IL-12.

Question 25

G6PD Deficiency

Answer 25

X-linked recessive

Anemia, lack of substrate for NADPH

Mostly asymptomatic

Manifestation same as CGD, formation of granulomas

Question 26

Chediak-Higashi Syndrome

Answer 26

Autosomal Recessive

Wheelchair bound, die by age 30

GIANT NEUTROPHILS, partial albinism, no NK activity

Granules have no Cathepsin G or Elastase

Defects in chemotaxis and degranulation

Recurrent pyogenic granuloma via bacteria infections, delayed diapedesis,

Question 27

Leukocyte Adhesion Deficiency

Answer 27

Neutrophil count double during infection

Don’t bind intercellular adhesion molecules on endothelial cells

Mutation of LFA-1 molecules CD11 and CD18

Delayed umbilical cord healing, slow wound healing, sever bacterial infections, failure to form pus

Question 28

Abnormalities of C1, C4, C2 manifest as:

Answer 28

Systemic Lupus erythematosus

Question 29

C3 Defects produce a clinical phenotype that is:

Answer 29

Indistinguishable from an Ab defect, but less frequent than Ab deficiencies

Question 30

Defects in late complement (C5-C9) are susceptible to:

Answer 30

Infections from Neisseria

Question 31

When to suspect alternative complement defects:

Answer 31

Deficiencies in Properdin, factor B/D present with severe Neisserial infections

Question 32

Factor H Deficiency

Answer 32

Alternative complement defect

Atypical hemolytic uremic Syndrome or glomerulonephritis

Question 33

C1 Esterase Inhibitor Deficiency

Answer 33

Hereditary angioedema

Production of bradykinin causes swelling

Question 34

Decay-Accelerating Factor Defects:

Answer 34

Paroxysmal nocturnal hemoglobinuria

Question 35

Defects in classic complement vs alternative complement typically present with:

Answer 35

Lupus vs. Neisseria Infection

Question 36

Best test for classical complement pathway defect

Answer 36

CH50

Absence of hemolysis on CH50 testing

SLE shows decreased results

Question 37

Best test for alternative complement defects:

Answer 37

AH50

Decreased AH50 = Deficiency in Factor B, D or properdin

Question 38

Primary CP Deficiency of C1 or C4 linked to:

Answer 38

Lupus and RA

Question 39

C2 Deficiency in young children:

Answer 39

Recurent URIs with Streptococcus pneumoniae