Immune Defense and Deficiency

Question 1

Immunodeficiency causes increased incidence and severity of what three conditions?

Answer 1

1) Infection 2) Malignancy 3)Autoimmunity

Question 2

What are some clues in a patient’s history that may indicate immunodeficiency?

Answer 2

Childhood infections; Family Hx; Behavior; Medications

Question 3

What are six aspects of infections may indicate immunodeficiency?

Answer 3

• More frequent - Respiratory (sinus, lung); PCP; Salmonella; VZV with HIV)
• More severe - bacteremia; ¬ tissue injury
• Prolonged - don’t resolve without therapy
• Recurrent - diarrhea; pneumonia; otitis; sinusitis; HSV; thrush [oral Candida]
• Poor response to Rx
• Unusual (opportunistic) pathogens - PCP; aspergillus; CNS Toxo; Listeria; Nocardia, Cryptococcus; Cryptosporidium

Question 4

What are four common sources of immunodeficiency?

Answer 4

• Malnutrition
• HIV/AIDS
• Age (very young/very old)
• Other (esp. medications – corticosteroids, chemotherapy, anti-TNF antibodies)

Question 5

What are the four basic components of the immune system?

Answer 5

1) Anatomic (skin, mucosal barriers) 2) Phagocytes (neutrophils and macrophages) 3) Cellular immunity (CD4+ T cells, CD8+ T cells (CTL), Natural killer cells (NK)) 4) Humoral (Specific antibodies (B cells) - Complement)

Question 6

What are the two broad ways in which the basic components of the immune system may become defective?

Answer 6

Decreased number/concentration Decreased function

Question 7

What are the frequency, genetic malfunction, and typical presenting age for primary immunodeficiency?

Answer 7

Rates are low (1: 10,000 live births) Most are single gene defects Most are present in childhood (e.g., XLA; SCID; Wiskott-Aldrich)

Question 8

What are the most common immunodeficiencies in adults?

Answer 8

* IgA deficiency * Common Variable Immunodeficiency (CVID) • IgG(2) subclass deficiency • Hyper-IgE syndrome (Job’s syndrome)

Question 9

What are the most common causes of immunodeficiency in the developing world?

Answer 9

Developing country - Malnutrition - HIV-1/AIDS - Measles - Age

Question 10

What are the most common causes of immunodeficiency in the developed world?

Answer 10

Developed country - Chronic steroids - HIV-1/AIDS - Cancer Therapy - Transplantation

Question 11

What are the three most common conditions that compromise immune defense by the skin, and what infecting agents are typically found?

Answer 11

Severe Eczema, Burns, IV Lines S. aureus, Ps. aeruginosa

Question 12

What are the two most common conditions that compromise immune defense in the lungs, and what infecting agents are typically found?

Answer 12

Cystic Fibrosis, Post-viral infection Ps. aeruginosa, S. pneumoniae, S. aureus

Question 13

What is the most common condition that compromises immune defense in the oral/GI tract, and what infecting agents are typically found?

Answer 13

Chemotherapy E. Coli, Candida

Question 14

What is the concentration of neutrophils that defines neutropenia?

Answer 14

For neutrophils, neutropenia with substantially increased risk of infection is classically defined as less than 500 PMN’s/uL, and particularly less than 100 PMN’s/uL.

Question 15

Chemotherapy induced neutropenia commonly leads to infections in what three areas?

Answer 15

• Intestine - GNR (E. coli), Candida; Enterococcus – Transcytosis (from epithelium); – Perirectal abscess
• Periodontal - Anaerobic abscess; oral streptococci
• Skin/Catheters - S. aureus (MRSA); Strept.; GNR (Ps. aer)

Question 16

What is the disorder in Chronic Granulomatous Disease and what are the common infections and infectious agents that result?

Answer 16

• Sufficient phagocyte number but decreased function • Uncommon (1 in 125,000); young children • Defect in NADPH oxidase (oxygen radicals decreased) • Recurrent skin abscesses, severe prolonged pneumonia, bone • Staph. aureus*, Serratia*, Nocardia, Salmonella, Aspergillus* • Diagnose clinically, family history, NBT test of PMN (*Risk for catalase+ organisms that destroy own oxygen radicals; not Streptococci [catalase -])

Question 17

What are six common causes of deficiency in cell-mediated immunity?

Answer 17

• Malnutrition • Immunotherapy/Oral steroids • Immunotherapy • Chemotherapy • Transplantation • HIV/AIDS

Question 18

What types of infections result from cell-mediated immunodeficiency?

Answer 18

• Bacterial • Fungal • Viral • Protozoan • Helminths

Question 19

What are the T-cell concentrations for early, intermediate, and advanced AIDS?

Answer 19

Cells / µL HIV-1 Stage Above 500 “Early” 200 - 500 “Intermediate” Under 200 “Advanced”; AIDS

Question 20

What cells are affected by HIV and how are they affected?

Answer 20

• T cell defects - - Low CD4+ T cells number - Decreased CD4+ T cell function
• NK cell dysfunction
• B cell dysfunction - Hypergammaglobulinemia/↑activation - Decreased memory B cells (IgD-; CD27+) - Decreased response to new antigens - High rates of autoimmunity
• Phagocytic function - PMN and macrophages - OK (High rates of mucosal Candida but no candidemia)

Question 21

What is the most common humoral immunodeficiency?

Answer 21

IgA deficiency most common (≈1:700) 1:300-1:1,000 adults

Question 22

What are the associations and consequences of IgA deficiency?

Answer 22

Family history of IgA def. or CVID

Limited increase in infection - (except with IgG2 defiency) - protection by compensatory IgM

Increased autoimmune, ± malignancy

Transfusion reactions (with anti-IgA)

Question 23

What are the three complement deficiencies and what infections commonly occur with each?

Answer 23

• C2 deficiency most common - C1-4 deficiency (classical pathway) present with pyogenic infections - C5-9 deficiency (terminal) show serious Neisserial infections

Question 24

How does Ig trigger destruction of antigens?

Answer 24

Pathogen-specific antibody typically binds by its pathogen-specific antigen-binding variable Fab region and mediates its effector functions through the ability of its constant Fc region to act as a bridge to other host defense mechanisms (e.g., complement, phagocytes, and NK cells).

Question 25

How do complement, phagocytes, and NK cells kill pathogens?

Answer 25

Recognition of Fc by these immune components (e.g., complement, phagocytes, and NK cells) induces fatal injuries to the pathogen, on which antibody defense is dependent. Complement: Complement-dependent assembly of transmembrane pores (membrane attack complexes [MAC; C5-9]), Natural Killer cells: Release of antimicrobial agents (e.g, cytokines such as IFN-γ) can activate phagocytes (neutrophils and macrophages), Phagocytes: Binding to and engulfment by phagocytes upon linkage of Complement (Green forks) with complement receptors (CR1/3) and Antibody Fc with Fc receptors on the pathogen and phagocyte, respectively.

Question 26

What is the most common serious primary defect in adults?

Answer 26

Common Variable Immunodeficiency

Question 27

What is the basic defect in CVID, the common infections, and age group most often affected?

Answer 27

• ↓IgG, IgM, IgA; nl number of B cells; “normal” T cells • Recurrent pyogenic sinopulmonary infections (esp. S. pneumoniae); less than ↓Ig children • Chronic diarrhea (G. lamblia; C. jejuni) - GI lymphoid hyperplasia; ↑ bacteremia • some ¬ PCP, fungi, mycobacteria; recurrent HSV • Increased risk of non-Hodgkins lymphoma and gastric cancers, and others. • Onset in teens or 20’s; men = women

Question 28

What are the four primary source of immune protection that may be defective in immunodeficiencies?

Answer 28

Anatomic Barrier

Phagocytic

Cellular

Humoral Immunity

Question 29

How do you test the cell number and function in phagocytic immunodeficiencies?

Answer 29

Test: - CBC and diff. (with smear)

Number: - PMN Less than 100-500

Function: Nitro Blue Tetrazolium

Question 30

How do you test the cell number and function in cellular immunodeficiencies?

Answer 30

Test:

• CBC with diff - Flow cytometry

Number:

• CD4 less than 500; Lymphocytes less than 1500

Function:

skin tests

Question 31

How do you test the cell number and function in humoral immunodeficiencies?

Answer 31

Test:

• Total Protein/albumin - Serum Protein Electrophoresis (SPEP) - Quant. IgG, IgM, IgA - CH50

Number:

• ↓globulin Total protein - ↓γ globulin SPEP - ↓ IgG, (M, A) Quant. - ↓CH50 CH50

Function:

• anti-A/B (RBC) - vaccination