Immunology - Lymphocytes

Question 1

Innate immunity

• Components
• Resistance
• Response to pathogens
• Physical barriers
• Secreted proteins
• Key features in pathogen recognition

Answer 1

• Components
  
  • Neutrophils, macrophages, monocytes, dendritic cells, NK cells (lymphoid origin), complement
• Resistance
  
  • Germline encoded
  • Resistance persists through generations, does not change within an organism’s lifetime
• Response to pathogens
  
  • Nonspecific
  • Occurs rapidly (minutes to hours)
• Physical barriers
  
  • Epithelial tight junctions, mucus
• Secreted proteins
  
  • Lysozyme, complement, CRP, defensins
• Key features in pathogen recognition
  
  • Toll-like receptors (TLRs): pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs).
  • Examples of PAMPs include LPS (gram-negative bacteria), flagellin (bacteria), ssRNA (viruses)

Question 2

Adaptive immunity

• Components
• Resistance
• Response to pathogens
• Secreted proteins
• Key features in pathogen recognition

Answer 2

• Components
  
  • T cells, B cells, circulating antibodies
• Resistance
  
  • Variation through V(D)J recombination during lymphocyte development
  • Microbial resistance not heritable
• Response to pathogens
  
  • Highly specific, refined over time
  • Develops over long periods
  • Memory response is faster and more robust
• Secreted proteins
  
  • Immunoglobulins
• Key features in pathogen recognition
  
  • Memory cells: activated B and T cells
  • Subsequent exposure to a previously encountered antigen –>Ž stronger, quicker immune response

Question 3

MHC I vs. II

• Both
• Loci
• Binding
• Expression
• Function
• Antigen loading
• Mode of transport to cell surface

Answer 3

• Both
  
  • MHC encoded by HLA genes.
  • Present antigen fragments to T cells and bind TCRs.
• Loci
  
  • I: HLA-A, HLA-B, HLA-C
  • II: HLA-DR, HLA-DP, HLA-DQ
• Binding
  
  • I: TCR and CD8
  • II: TCR and CD4
• Expression
  
  • I: Expressed on all nucleated cells; Not expressed on RBCs
  • II: Expressed only on APCs
• Function
  
  • I: Present endogenously synthesized antigens (e.g., viral) to CD8+ cytotoxic T cells
  • II: Present exogenously synthesized proteins (e.g., bacterial proteins, viral capsid proteins) to T-helper cells
• Antigen loading
  
  • I: Antigen peptides loaded onto MHC I in RER after delivery via TAP peptide transporter
  • II: Antigen loaded following release of invariant chain in an acidified endosome
• Mode of transport to cell surface
  
  • I: β2-microglobulin
  • II: Unknown

Question 4

HLA subtypes associated with diseases

• A3
• B27
• DQ2/DQ8
• DR2
• DR3
• DR4
• DR5

Answer 4

• A3
  
  • Hemochromatosis.
• B27
  
  • Psoriatic arthritis, Ankylosing spondylitis, arthritis of Inflammatory bowel disease, Reactive arthritis (formerly Reiter syndrome).
    
    • PAIR.
  • Also known as seronegative arthropathies.
• DQ2/DQ8
  
  • Celiac disease.
• DR2
  
  • Multiple sclerosis, hay fever, SLE, Goodpasture syndrome.
• DR3
  
  • Diabetes mellitus type 1, SLE, Graves disease.
• DR4
  
  • Rheumatoid arthritis, diabetes mellitus type 1.
  • There are 4 walls in a “rheum” (room).
• DR5
  
  • Pernicious anemia Ž–> vitamin B12 deficiency, Hashimoto thyroiditis.

Question 5

Natural killer cells

Answer 5

• Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells.
• Only lymphocyte member of innate immune system.
• Activity enhanced by IL-2, IL-12, IFN-β, and IFN-α.
• Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of class I MHC on target cell surface.
• Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating the NK cell).

Question 6

Major functions of B and T cells

• B cell functions
• T cell functions

Answer 6

• B cell functions
  
  • Recognize antigen—undergo somatic hypermutation to optimize antigen specificity.
  • Produce antibody—differentiate into plasma cells to secrete specific immunoglobulins.
  • Maintain immunologic memory—memory B cells persist and accelerate future response to antigen.
• T cell functions
  
  • CD4+ T cells help B cells make antibody and produce cytokines to activate other cells of immune system.
  • CD8+ T cells kill virus-infected cells directly.
  • Delayed cell-mediated hypersensitivity (type IV).
  • Acute and chronic cellular organ rejection.
  • Rule of 8: MHC II × CD4 = 8; MHC I × CD8 = 8.

Question 7

Differentiation of T cells

• Positive selection
• Negative selection

Answer 7

• Positive selection
  
  • Thymic cortex.
  • T cells expressing TCRs capable of binding surface self MHC molecules survive.
• Negative selection
  
  • Medulla.
  • T cells expressing TCRs with high affinity for self antigens undergo apoptosis.

Question 8

T and B cell activation

• Antigen-presenting cells (APCs)
• Two signals are required for T cell activation

Answer 8

• Antigen-presenting cells (APCs):
  
  • B cells
  • Macrophages
  • Dendritic cells.
• Two signals are required for T cell activation:
  
  • B cell activation
  • Class switching.

Question 9

Naive T cell activation

Answer 9

1. Foreign body is phagocytosed by dendritic cell.
2. Foreign antigen is presented on MHC II and recognized by TCR on Th (helper) cell.
   Antigen is presented on MHC I to Tc (cytotoxic) cells (signal 1).
3. “Costimulatory signal” is given by interaction of B7 and CD28 (signal 2).
4. Th cell activates and produces cytokines.
   Tc cell activates and is able to recognize and kill virus-infected cell.

Question 10

B cell activation and class switching

Answer 10

1. Helper T cell activation.
2. B cell receptor-mediated endocytosis
   
   • Foreign antigen is presented on MHC II and recognized by TCR on Th cell (signal 1).
3. CD40 receptor on B cell binds CD40 ligand on Th cell (signal 2).
4. Th cell secretes cytokines that determine Ig class switching of B cell.
   
   • B cell activates and undergoes class switching, affinity maturation, and antibody production.

Question 11

Helper T cells

• Th1 cell
  
  • Secretes…
  • Function
  • Inhibited by…
• Th2 cell
  
  • Secretes…
  • Function
  • Inhibited by…
• Macrophage-lymphocyte interaction
• CD4

Answer 11

• Th1 cell
  
  • Secretes IFN-γ
  • Activates macrophages and cytotoxic T lymphocytes (CTLs)
  • Inhibited by IL-4 and IL-10 (from Th2 cell)
• Th2 cell
  
  • Secretes IL-4, IL-5, IL-6, IL-13
  • Recruits eosinophils for parasite defense and promotes IgE production by B cells
  • Inhibited by IFN-γ (from Th1 cell)
• Macrophage-lymphocyte interaction
  
  • Macrophages release IL-12, which stimulates T cells to differentiate into Th1 cells.
  • Th1 cells release IFN-γ to stimulate macrophages.
• CD4
  
  • Helper T cells have CD4, which binds to MHC II on APCs.

Question 12

Cytotoxic T cells

Answer 12

• Kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis.
• Release cytotoxic granules containing preformed proteins
  
  • Perforin—helps to deliver the content of granules into target cell
  • Granzyme B—a serine protease, activates apoptosis inside target cell
  • Granulysin—antimicrobial, induces apoptosis
• Cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells.

Question 13

Regulatory T cells

Answer 13

• Help maintain specific immune tolerance by suppressing CD4 and CD8 T-cell effector functions.
• Identified by expression of cell surface markers CD3, CD4, CD25 (a chain of IL-2 receptor), and transcription factor FOXP3.
• Activated regulatory T cells produce anti-inflammatory cytokines like IL-10 and TGF-β.

Question 14

Antibody structure and function

• Variable part
• Heavy chain
• Light chain
• Fab
• Fc
• Antibody diversity is generated by:

Answer 14

• Variable part of L and H chains recognizes antigens.
• Heavy chain contributes to Fc and Fab fractions.
• Light chain contributes only to Fab fraction.
• Fab
  
  • Antigen-binding fragment
  • ƒƒDetermines idiotype
    
    • Unique antigen-binding pocket
    • Only 1 antigenic specificity expressed per B cell
• Fc
  
  • ƒƒConstant
  • ƒƒCarboxy terminal
  • ƒƒComplement binding
  • ƒƒCarbohydrate side chains
  • ƒƒDetermines isotype (IgM, IgD, etc.)
  • Fc portion of IgM and IgG fixes complement
• Antibody diversity is generated by:
  
  • Random “recombination” of VJ (light-chain) or V(D)J (heavy-chain) genes
  • Random combination of heavy chains with light chains
  • Somatic hypermutation (following antigen stimulation)
  • Addition of nucleotides to DNA during recombination (see 1st entry in this list) by terminal deoxynucleotidyl transferase

Question 15

Immunoglobulin isotypes

Answer 15

• Mature B lymphocytes express IgM and IgD on their surfaces.
• They may differentiate in germinal centers of lymph nodes by isotype switching (gene rearrangement; mediated by cytokines and CD40 ligand) into plasma cells that secrete IgA, IgE, or IgG.

Question 16

IgG

Answer 16

• Main antibody in 2° (delayed) response to an antigen.
• Most abundant isotype in serum.
• Fixes complement, crosses the placenta (provides infants with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses.

Question 17

IgA

Answer 17

• Prevents attachment of bacteria and viruses to mucous membranes
  
  • Does not fix complement.
• Monomer (in circulation) or dimer (when secreted).
• Crosses epithelial cells by transcytosis.
• Most produced antibody overall, but released into secretions (tears, saliva, mucus) and early breast milk (known as colostrum).
• Picks up secretory component from epithelial cells before secretion.

Question 18

IgM

Answer 18

• Produced in the 1° (immediate) response to an antigen.
• Fixes complement but does not cross the placenta.
• Antigen receptor on the surface of B cells.
• Monomer on B cell or pentamer when secreted.
• Shape of pentamer allows it to efficiently trap free antigens out of tissue while humoral response evolves.

Question 19

IgD

Answer 19

• Unclear function.
• Found on the surface of many B cells and in serum.

Question 20

IgE

Answer 20

• Binds mast cells and basophils
  
  • Cross-links when exposed to allergen, mediating immediate (type I) hypersensitivity through release of inflammatory mediators such as histamine.
• Mediates immunity to worms by activating eosinophils.
• Lowest concentration in serum.

Question 21

Antigen type and memory

• Thymus-independent antigens
• Thymus-dependent antigens

Answer 21

• Thymus-independent antigens
  
  • Antigens lacking a peptide component (e.g., lipopolysaccharides from gram-negative bacteria)
  • Cannot be presented by MHC to T cells.
  • Weakly or nonimmunogenic
  • Vaccines often require boosters (e.g., pneumococcal polysaccharide vaccine).
• Thymus-dependent antigens
  
  • Antigens containing a protein component (e.g., diphtheria vaccine).
  • Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40–CD40 ligand interaction).