Hem-Onc2: Primary Immunodeficiencies

Front 1

Causes of Immunocompromise

Back 1

Loss of physical barriers - skin (burn victims), oncology
Medications - reduction in cell number or function
Acquired or congenital defects in cell number
Acquired or congenital defects in cell function

Front 2

Innate and Adaptive Immunity role, parts, reactions

Back 2

Innate - defense mechanisms present before infection. Includes epithelial barriers such as GI or lung tract, complement system, many cell types. Reactions include inflammation, anti-viral defense, phagocytosis

Adaptive immunity - activated by pathogens or the innate response. Develops after exposure to pathogens. Consists of lymphocytes and products. 2 cell types. Humoral - Ab mediated (B-Cells) and Cellular (T-cells)

Front 3

Cells of innate immunity and role

Back 3

Neutrophils: Phagocytosis; production of bactericidal ROS

Macrophages: Phagocytosis; Ag presentation; clearance; recruit additional phagocytic cells

Dendritic cells: Ag presentation; phagocytosis; kill virally infected cells

NK cells: Kill virally infected cells, tumor cells, foreign cells

Front 4

Cells of adaptive immunity and role

Back 4

B cells: Produce antibodies which then opsonize bacteria

CD8 T cells: cytolytic

CD4 T cells: Help B cells class switch; helps CD8 cells kill

Immunodeficiencies in T cells can alter B cell immune system as well

Front 5

Deficits in Cellular immunity vs Humoral immunity

Back 5

CD4 Defects - Loss of Ig production; opportunistic infection

CD8 defects - lack of killer function; holes in tumor surveillance, may be at increased risk for cancer development; risk of viral infection

Humoral immunity
B cells defect - inability to opsonize bacteria, esp respiratory, skin and encapsulated organisms

Front 6

Measuring immune function
a) Quantitative (with cytommetry markers)
b) Nonspecific function
c) Specific function

Back 6

a) Absolute lymphocyte count (1800 normal, 6700 in infants). Tells ONLY number NOT function
CD3 - T cells, CD4 for helpers, CD8 for killers
CD19 - B cells
CD16, CD56 - NK cells

b) Nonspecific function -
T cell mitogen proliferation
B cell - quantitative Ig's, IgG subclasses; in general Ab production will req. B cells and intact T cells

c) Specific function
T-cell - proliferation to antigens (tetanus and candida)
B cells - Antigen specific antibodies - Carbohydrate antigen (pneumovax titiers) or protein antigen (tetanus titers)

Think about these tests if have Hx of opportunistic infections, failure to thrive, etc.

Front 7

What does Ab production require

Back 7

B cells and intact/functional T cells (esp. CD4 T cells)

Front 8

3 most common Ig's, structure, amount and placental transfer, when is it maternal vs child

Back 8

IgM – 5-10%, No placental transfer, pentameric structure

IgG – 75-85%, placental transfer, monomeric structure
Measuring IgG in a 2 month old is still just measuring maternal antibody production
IgG physiologic nadir – 2-6 months of age; more accurate for what child is producing on their own

IgA – 5-15%, No placental transfer, mono-dimeric structure

Front 9

Signs to suspect a Primary Immunodeficiency, History signs, PE signs,

Back 9

Present with common and/or nonspecific signs/symptoms
Early in life, opportunistic infections, difficult to treat, may see autoimmune, allergic reactions (mostly recurrent ENT and airway infections)
Family history can be a clue (esp. if developed a lymphoma)

History: Look for recurrent bacterial infections, severe ones, opportunistic pathogens, failure to thrive, diarrhea, prolonged candidasis or thrush, atypical autoimmune disease, skin abscesses

PE: dysmorphic features, severe eczema, abnormal hair, telangiectasia, ataxia, oral ulcers, gum disease, abnormal wound healing, LAD, vasculitis, absence of immune tissue (NO THYMIC SHADOW)

Front 10

Potential categories for primary immunodeficiencies

Back 10

Combined B and T cell immunodeficiencies
Primary antibody deficiencies
Diseases of immune dysregulation
Phagocytotic defects
Innate immunity defects
Autoinflammatory disorders
Complement disorders
Other

MOST are Antibody def (50%), Then combined antibody and cellular immunodeficiencies, phagocytic dysfunction

Complement deficiencies most rare

Front 11

Congenital Immunodeficiencies Absent vs Defective T-Cell, B-Cell and Neutrophil Diseases

Back 11

a. T-Cell
Absent: SCID
Defective: WAS
b. B-Cell
Absent: XLA
Defective: CVID
c. Neutrophils
Absent: Kostmann’s
Defective: CGD

Front 12

Severe Combined Immunodeficiency Syndrome Pathology, Hallmark, Symptoms, Subtypes w/ molecular defects, diagnosis, management

Back 12

Group of syndromes having in common profound disturbances of both B and T cells with variable NK cells. B-cells if present do not function. ABSENT functional autologous T-cells. eg. "bubble boy"

Often fatal by age 2 due to overwhelming infection if not treated

X-linked cytokine common gamma chain most common type (BOYS). but some AR forms

Hallmark: T cell Lymphopenia in combination with hypo or agammaglobulinemia

Sx: Failure to thrive, diarrhea, recurrent infections, thrush, absent thymic shadow, low/absent T cells, lack of IgG's

Types:
1) T-B+ (NK variable) - No T, some B cells, variable NK
a) Cytokine common gamma chain (X-linked) - MOST COMMON. Defective IL-7 receptor alters T-cell develop. IL15 is also altered (NK development)
b) JAK3 - needed for signal transduction through cytokine common gamma chain
c) IL-7 receptor chain alpha

2) T-B- (NK variable) - NO T, NO B
AR (equal for genders)
a) Adenosine deaminase (ADA) - toxic metabolites accumulate leading to absence of lymphocytes
b) RAG1 or 2 def
c) Reticular dysgenesis - lack stem cells in addition to No T and No B. So see agranulocytosis

Diagnosis: History, ALC low or absent T cells, Lymphocyte proliferation studies show absent T cells prolif to mitogens. Quantitative Ig's and specific Ab response if vaccinated to check B-cells

Management: IgG replacement, PCP prophylaxis, Irradiate blood products to avoid GVHD, enzyme replacement. STEM CELL TRANSPLANT CURATIVE. Gene therapy

Front 13

SCID with agranulocytosis as well

Back 13

suspect Reticular dysgenesis. AR form

Front 14

DiGeorge Syndrome Pathology, defects, molecular

Back 14

A form of T-B+ SCID

Pathology: Failure of 3rd and 4th pharyngeal pouches to develop so thymic epithelium not produced leading to immunodef and loss of T-cell immunity

Defects: Loss of T-cell immunity. Also affects great vessels (cardiac defects), parathyroids and jaw

Molecular: Chromosome 22q11.2, sporadic inheritance

Front 15

ASE in gene therapy for SCID

Back 15

successful but 20% of pts develop T cell Acute lymphocytic leukemia/lymphoma due to activation of oncogenes by retrovirus

stem cell transplant best curative

Front 16

X-linked Agammaglobulinemia Pathology, Hallmark, Clinical, Management

Back 16

Failure of B-cell development, Bruton's tyrosine kinase gene mutated - needed for intracellular signal transduction in pre-B cells for maturation to B cells and plasma cells. ARRESTED PRE-B cells in marrow

Do well with maternal IgG until declines around 3mos-2yrs

Hallmark: LOW TO ABSENT IgG, IgM, IgA with INTACT T-cell immunity

Clinical:
Recurrent pyogenic infections (pneumonia, otitis, ear infections, sinusitis, sepsis, absecces) - usually H. influenzae, strep or staph b/c can't opsonize
CAN HANDLE viral, fungal or parasites EXCEPT enterovirus
usually no failure to thrive unless have enterovirus or bronchietasis

Management: IgG replacement

Front 17

Infections XLA can and can't handle

Back 17

CAN"T HANDLE pyogenic infections (pneumonia, otitis, ear infections, sinusitis, sepsis, absecces) - usually H. influenzae, strep or staph b/c can't opsonize
CAN HANDLE viral, fungal or parasites EXCEPT enterovirus

Enterovirus from live polio vaccine can lead to viremia, encephalitis, paralysis and death

Front 18

Wiscott Aldrich Syndrome Pathology, Inheritance, Triad, Management

Back 18

Defective T-cells, WAS protein gene mutated. Combined B and T cell effect b/c B cells need T cells to activate them

Triad: Immunodeficiency, Eczema/atopy, Thrombocytopenia (small platelets too)

Management: stem cell transplant, risk of lymphoma as an adult which may show up in FHx

Front 19

Common Variable Immunodeficiency, Pathology, Clinical

Back 19

Heterogeneous, relatively common, unknown defects. variable T cell number and function

Usually not picked up immediately and not in first year of life

Hypogammaglobulinemia - may affect all Ig's or just IgG. Often just see DECREASED response to vaccinations

Clinical: recurrent sinopulmonary infections, 20% have RECURRENT HERPES infection, increased occurence of autoimmune disorders. Increased RISK of LYMPHOID and GASTRIC cancers

Management: IgG replacement and aggressive treatment of infections. Depending on location in spectrum may need prophylaxis for things like pneumocystis pneumonia

Front 20

Selective IgA Deficiency, Pathology, Genetics, Clinical

Back 20

Common, familial or acquired due to infection. ASSOCIATED with CVID. Unknown basis

Hallmark: LOW SERUM and SECRETORY IgA (Other Ig's ok)

Produces autoantibodies and antibodies to IgA, can get anaphylaxis to blood or plasma products with IgA

Clinical: May be asymptomatic, Recurrent sinopulmonary infections and diarrhea, ATOPY, Autoimmune illness (SLE, RA)

Front 21

Chronic Granulomatous Disease, normal neutrophil fxn, Genetics of CGD, Pathology, Clinical, Opportunistic organisms, Test, Management

Back 21

Neutrophils - roll along endothelial surface, become activated and adhere, migrate across to chemotactic stimulus, kill and remove microbes or dead cells

Genetics: X-linked and AR forms, defects in NADPH oxidase. X-linked (most common) is for GP91 PHOX and MEMBRANE defects. AR are for PHOX (22, 67, 47) genes and affect cytoplasm

Clinical:
Skin infections, pneumonias, lymphadenitis
GRANULOMAS form
Aspergillus and B. cepecia most troublesome but Staph most common

CAN KILL catalase negative organisms (NO RECURRENT STREP)

Test: Absent or decreased NADPH oxidase activity as tested by NITROBLUE TETRAZOLIUM TEST. Negative in CGD, positive in normal (blue)

Management:
Bactrim for pneumocystis prophylaxis and itraconazole for fungal prophylaxis, treat infections

Front 22

Organisms that distinguish by being able to handle or not
a) CGD
b) CVID
c) WAS
d) XLA
e) SCID

Back 22

a) CAN handle Strep normally (catalase -) but NOT staph, aspergilllus and B. cepecia. Skin infections and pneumonia
b) Some have herpes association. Get sinopulmonary infections
c) Eczema, no specific organisms
d) Low Ig's, So get Pyogenic infections (pneumonia, ear, sinusitis, abscess). H. influenza, strep or staph. CAN HANDLE viral, fungal and parasites except enterovirus
e) SCID - get everything, can't handle anything