Immune Defense and Deficiency

Question 1

Definition of immunity & relationship to immunology

Answer 1

• Derived from Latin word “immunitas” = “exemption”
• Protection against disease, but not necessarily infection
• More rapid & greater response to subsequent exposure
• “Natural” and acquired immunity exist
• Immunology = study of mechanisms of immunity against infection and adverse effects of immune response

Question 2

4 components of immune function

Answer 2

1. Anatomic
   
   1. Skin
   2. Mucosal barriers
2. Phagocytes
   
   1. PMNs
   2. Macrophages
3. Cellular immunity
   
   1. CD4+ T cells
   2. CD8+ T cells
   3. NK cells
4. Humoral immunity
   
   1. Antibodies from B cells
   2. Complement

Question 3

Immunodeficiency: clinical clues

Answer 3

• History: childhood infections, family history, behavior, prescribed medications
• Infections: increased frequency, increased severity, increased duration, poor response to therapy, unusual pathogens (including opportunistic pathogens)
  
  • Respiratory infections will be more frequent
  • More severe: bacteremia, increased tissue injury
• References for # of infxns/year:
  
  • Age 0-10: 6-8 URI/year
  • Age 0-3: < 6 episodes of otitis media + 2 episodes of gastroenteritis/year

Question 4

Immunodeficiency: clinical clues

Answer 4

• Detect decreased number/function of cells
• Neutrophils (PMNs)
  
  • Nitroblue tetrazolium (NBT) - doesn’t turn blue with CGD
  • < 500 PMNs = neutropenia –> increased risk of infection
• T cells
  
  • CD4 for HIV
  • CBC simply gives B cells vs T cells - doesn’t break down constituents of each group
• Antibody
  
  • Assay Ig levels or other immunoglobulins

Question 5

Primary immunodeficiency

Answer 5

• Rare (1/10,000 live births)
• > 100 defects
• 70% humoral
• Most are single gene defects
• Most present in childhood - SCID, etc.
• Adults:
  
  • IgA deficiency
  • CVID
  • IgG subclass deficiency
  • Hyper IgE (Job’s syndrome)

Question 6

Secondary immunodeficiency

Answer 6

• Developing countries
  
  • Malnutrition: most common worldwide
  • HIV-1/AIDS: significant cause of disease worldwide
  • Measles
  • Age: extremes are risk factors, many affect young and elderly
• Developed countries
  
  • Chronic steroids
  • HIV-1/AIDS
  • Cancer therapy
  • Transplantation

Question 7

Consequences of immunodeficiency

Answer 7

• Increased incidence and severity of:
  
  • Infection
  • Malignancy
  • Autoimmunity

Question 8

Anatomic immunodeficiency: types and associated bugs

Answer 8

• Skin
  
  • Primary: eczema
  • Secondary: burns, IV
  • Bugs: S. aureus, P. aeruginosa
• Lung
  
  • Primary: Cystic fibrosis
  • Secondary: post-viral
  • Bugs: P. aeruginosa, S. pneumoniae, S. aureus
• GI/Oral
  
  • Primary: n/a
  • Secondary: chemo drugs
  • Bugs: E. coli, Candida, Enterococcus

Question 9

Phagocytic immunodeficiency: neutropenia

Answer 9

• Neutropenia = < 500 PMNs/uL
  
  • Particularly when < 100 PMNs/uL
• Intestinal:
  
  • Gram (-) rods: E. coli, Candida, Enterococcus
• Periodontal anaerobic abscesses: oral Streptococci
• Skin/catheters: MRSA, Strep, Pseudomonas

Question 10

Phagocytic immunodeficiency: CGD

Answer 10

• Sufficient # but decreased function of phagocytes
  
  • ​Defect in NADPH oxidase (ROS decrease)
• Risk for catalase (+) organisms that destroy O2 radicals
• Specific bugs: S. aureus, Serratia, Nocardia, Salmonella, Aspergillus
• Recurrent skin abscesses, severe prolonged pneumonia, bone infections

Question 11

Diagnosis of CGD

Answer 11

• Labs:
  
  • Nitroblue tetrazolium (NBT) test
  • Tests PMN production of reactive oxygen species (ROS)
  • Applied clear
  • If reduced by ROS –> cells turn blue
    
    • Blue = ROS
• Clinically:
  
  • Family history

Question 12

Cell-mediated immunodeficiency

Answer 12

• WBC x % lymphocytes = lymphocyte number
  
  • Should be 1500-4000 in adults
• Most common cause: malnutrition
• HIV: associated with combined immune defects
  
  • Low CD4+ number and decreased function
  • NK dysfunction
  • Decreased memory B cells, decreased response to new antigens, high rates of autoimmunity
  • PMNs and macrophage functions preserved

Question 13

Cell-mediated immunodeficiency: bacterial infections

Answer 13

• Let My Legion Never Surrender:
  
  • Listeria
  • Mycobacteria
  • Legionella
  • Nocardia
  • Salmonella

Question 14

Cell-mediated immunodeficiency: fungal infections

Answer 14

• Cryptococcus
• Pneumocystis
  
  • Can prevent with TMP/SMX
• Aspergillus
• Candida
• Cocci immitis

Question 15

Cell-mediated immunodeficiency: viral infections

Answer 15

• HSV
• Varicella
• CMV
• Adenovirus

Question 16

Cell-mediated immunodeficiency: protozoal and helminth infections

Answer 16

• Protozoan
  
  • Toxoplasma
  • Cryptosporidium
• Helminths
  
  • Strongyloides

Question 17

Humoral mediated immunodeficiency

Answer 17

• Hypogammaglobulinemia
• Serum protein electrophoresis: used to visualize Ig deficient states
• Selective IgA deficiency
• Common variable immunodeficiency (CVID)

Question 18

Selective IgA deficiency

Answer 18

• Most common primary immunodeficiency
• Little increase in infection rate unless also IgG2 deficient
• Increased autoimmunity +/- malignancy

Question 19

Common variable immunodeficiency (CVID)

Answer 19

• Recurrent sinopulmonary infections
• Chronic diarrhea
• Decreased levels of IgG, IgM, and IgA
• Normal # of B cells
• “Normal” T cells
• Increased risk of non-Hodgkins lymphoma and gastric cancers

Question 20

Gammaglobulins

Answer 20

• Represent all antibodies - IgM + IgG + IgD + IgA + IgE
• IgG1
  
  • Recognize proteins
  • 70% of IgG
• IgG2
  
  • Recognize polysaccharides (e.g. capsules of S. pneumo and H. influenzae)
  • 20% of IgG
• IgM
  
  • Blood/mucosal
  • Very opsonic
• IgA1,2
  
  • Mucosal > blood

Question 21

Complement

Answer 21

• 3 activation pathways, all converge on C3 - C5-9 forms membrane attack complex
  
  • Classical
  • Alternative
  • Lectin
• Acts in concert with Ab to opsonize bacteria and facilitate killing of Gram (-) organisms by lysis or phagocytosis
• Several complement deficiencies possible
• C2 complement deficiency most common
• C1-4 deficiencies –> pyogenic infetions
• C5-9 deficiencies –> Neisseria infections