Immunology Physiology

• -Secondary lymphoid structure
• -many afferents
• -one or more efferents
• -encapsulated
• -trabeculae

• Functions:
• -nonspecific filtration by macrophages
• -storage/activation of B and T cells
• -antibody production

• Three Areas:
• 1. Follicle
• 2. Medulla
• 3. Paracortex
• 

• -site of B cell localization and proliferation
• -in outer cortex

• Primary Follicles
• -dense and dormant

• Secondary Follicles
• -pale central germinal centers
• -active
• 

• Medullary cords:
• -closely packed lymphoctes and plasma cells

• Medullary sinuses:
• -communicate with efferent lymphatics
• -contain reticular cells and macrophages

• -region of cortex between follicles and medulla
• -contains high endothelial venules (HEV) through which B and T cells enter from the blood

• Functions:
• -houses T cells
• -becomes enlarged during extreme cellular immune responses (viral)

**Not well developed in patients with DiGeorge syndrome

• AXILLARY:
• -upper limb
• -lateral breast

• CELIAC:
• -stomach

• SUPERIOR MESENTERIC:
• -Duodenum
• -Jejunum

COLIC --> INFERIOR MESENTERIC:-Sigmoid Colon

• INTERNAL ILIAC:
• -Rectum
• -Anal canal above pectinate line

• SUPERFICIAL INGUINAL:
• -Anal canal below pectinate line

• SUPERFICIAL AND DEEP PLEXUSES --> PARA-AORTIC:
• -Testes

• SUPERFICIAL INGUINAL:
• -Scrotum
• -Thigh (superficial)

• POPLITEAL:
• -lateral side of dorsal foot

• RIGHT LYMPHATIC DUCT:
• -drains R arm, chest and half of head

• THORACID DUCT:
• -drains everything else

Long, vascular channels in red pulp with fenestrated "barrel hoop" basement membrane

Macrophages found nearby (remove encapsulated bacteria)

• PALS (periarterial lymphatic sheath)
• -within white pulp
• -T cells

B cells found within follicles in the white pulp

• Function:
• -T cell differentiation and maturation

• Structure:
• -encapsulated

• Cortex:
• -dense with immature T cells
• -POSITIVE SELECTION (MHC Restriction)

• Medulla:
• -pale with mature T cells
• -epithelial reticular cells (Hassall's corpuscles)
• -NEGATIVE SELECTION (nonreactive to self)
• 

• Embryonic Origins:
• -epithelium of 3rd branchial pouch
• *(lymphocytes are of mesenchymal origin)

-receptors are germline encoded

-response to pathogens is fast and nonspecific

-no memory

• Cells:
• -neutrophils
• -macrophages
• -dendritic cells
• -NK cells (lymphoid origin)
• -complement

-receptors undergo V(D)J recombination

• -response is slow on first exposure
• -memory response is fast and more robust

• Cells:
• -T cells
• -B cells
• -circulating antibody

• -HLA-A, HLA-B, HLA-C
• -binds TCR and CD8

• Expression:
• -all nucleated cells
• -not on RBCs

• -Antigen loaded in RER with mostly intracellular peptides
• 
• -mediates viral immunity

• -pairs with beta2-microglobulin
• 

• HLA-DR, HLA-DP, HLA-DQ
• -binds TCR and CD4

• Expression:
• -only on APCs

• Antigen is loaded following release of invariant chain in acidified endosome (HLA-DM)
• 

• 1. Make antibody
•      -opsonize bacteria
•      -neutralize viruses (IgG)
•      -activate C' (IgM, IgG)
•      -sensitize mast cells (IgE)

• 2. Allergy
•      -Type I hypersensitivity
•      -IgE mediated

• 3. Hypersensitivity, IgG mediated
•      -Type II (cytotoxic)
•      -Type III (immune complex)

• 4. Organ Rejection
•      -hyperacute
•      -humorally mediated acute and chronic

(Innate immunity) - viruses/tumors

-Use perforin and granzymes to induce apoptosis of virally infected cells and tumors

-Only lymphocyte member of innate immune system - (so Jamie should have done this card)

-Activity enhanced by IL-12, IFN-β, and IFN-α


-Induced to kill when exposed to nonspecific activation signal and/or to an absence of class I MHC on target cell surface

• -sit in the tissue as immature cells, constantly phagocytosing
• -TLR activation induces maturation
• -Mature DCs travel to the LN via afferent lymphatics
• -Present antigen to T cells
• -No direct killing of pathogens
• -DCs make cytokines
• 

Phagocytic cells derived from monocytes

• Many tissues have resident macrophages
• -Microglial cells (CNS)
• -Kupffer cells (liver
• -Alveolar macrophages (lungs)
• -Osteoclasts (bone)

• "foot soldiers"; phagocytose
• -70% of circulating WBCs
• -first to arrive at infection
• -low proliferattive potential
• 

Neutrophil extracellular traps (NETs) - made of DNA and anti-microbial products

• Extravasation:
• 1. Rolling
• 2. Activation
• 3. Arrest/adhesion
• 4. Transendothelial migration

1. Helper T cell activation

2. B cell receptor-mediated endocytosis --> foreign antigen presented on MHC II and recognized by TCR on Th cell (SIGNAL 1)

3. CD40R on B cells binds CD40L on Th cell (SIGNAL 2)

4. Th cell secretes cytokines that determine Ig class switching

5. B cell activates and undergoes class switching, affinity maturation and antibody production

• Light chain
• -contributes to Fab fraction
• -has V and J genes

• Heavy chain
• -contributes to Fab and Fc fraction
• -has V, D and J genes

• Variable region
• -parts from L and H chains
• -recognizes antigens

• Fc portion
• -Constant portion
• -IgM and IgG fixes C'

• Fab:
• -antigen-binding fragment
• -determines idiotype
• -unique antigen binding pocket
• -only one antigen specificity/B cell

• Fc:
• -Constant
• -Carboxy terminal
• -C' binding at C_H2 (IgG and IgM)
• -Carbohydrate side chains
• -determines isotype (IgM, IgD etc)
• 

1. Random recombination of VJ (L) and VDJ (H) genes

2. Random combination of H chains with L chains

3. Somatic hypermutation (following Ag stimulation)

4. Addition of Ntds during recombination by terminal deoxynucleotidyl transferase (TdT)

• 1. Opsonization
•      -Ab promotes phagocytosis

• 2. Neutralization
•      -Ab prevents bacterial adherence

• 3. C' Activation
•      -enhances opsonization and lysis

-mature B cells express IgM and IgD

-may differentiate by isotype switching to plasma cells (mediated by cytokines and CD40L)

-plasma cells may express IgA, IgE or IgG

• Types:
• -IgG
• -IgA
• -IgM
• -IgD
• -IgE

-main antibody in secondary (delayed) response to antigen

-most abundant isotype

• Functions:
• -fixes C'
• -passive immunity for infants (crosses placenta)
• -opsonizes bacteria
• -neutralizes bacterial toxins
• -neutralizes viruses

• -Found in secretions (tears, saliva, mucus)
• -Found in early breast milk (called colostrum)

• -Monomer in circulation
• -Dimer when secreted

• -crosses epithelial cells by transcytosis
• -picks up secretory component from epithelial cells before secretion
• 

• Functions:
• -prevents bacterial and viral attachment to mucus membranes
• -does NOT fix C'

-produces the primary (immediate) response to antigen

-does NOT cross placenta

-antigen receptor on the surface of B cells

-monomer on B cell, or pentamer

• Functions:
• -fixes C'
• -shape of pentamer allows efficient trapping of free antigens out of tissue while humoral response evolves

-Unclear function

-Found on surface of many B cells and in serum

-lowest concentration in serum

• Functions:
• -Type I Hypersensitivity (binds mast cells and basophils, cross-links when exposed to allergen --> release of mediators like histamine)
• -immunity to worms by activating eosinophils

• 1. Thymus-Independent Antigens
• -lack a peptide component
• -cannot be presented by MHC to T cells
• -EG: LPS, polysaccharide capsular antigen
• -stimulate release of antibodies
• -do NOT result in immunologic memory

• 2. Thymus-Dependent Antigens
• -antigens containing a protein component
• -EG: diptheria vaccine
• -Class switching and memory occur (due to B cell interaction with Th cells, CD40-CD40L)

1. Type IV Hypersensitivity (delayed cell-mediated)

• CD4 T cells:
• 1. Help B cells make antibody
• 2. Produce cytokines to activate other cells of the immune system

• CD8 T cells:
• 1. Directly kill virus infected cells
• 2. Acute and chronic cellular organ rejection

1. T cell precursor (DN) in bone marrow migrates to thymus

2. Cell rearranges and expresses beta chain (with preTalpha), if successful proliferates, if unsuccessful dies

3. Cell rearranges and expresses alpha chain, if successful proliferates, if unsuccessful dies

4. DP T cell expresses rearranged TCR, CD8 and CD4

5. DP cells undergo positive selection in cortex

6. SP cells undergo negative selection in medulla

7. Mature T cells leave the thymus for the LN

• -occurs in the thymic cortex
• -T cells with TCRs capable of binding self MHC survive

• -occurs in thymic medulla
• -T cells expressing TCRs with high affinity for self antigens undergo apoptosis

1. Dendritic cells (only APC that can activate naive T cell)

2. Macrophages

3. B cells

1. Foreign body phagocytosed by DC

2. SIGNAL 1: Foreign antigen is presented on MHC II and recognized by TCR on Th cell OR presented on MHC I and recognized by TCR on CTL

3. SIGNAL 2: "costimulatory signal" given by interaction of B7 and CD28

• 4. Th cell activates and produces cytokines
• 5. CTL activates and kills virus infected cell

1. Th1

2. Th2

3. Treg

• -secrete IFNg
• -activate macrophages
• -inhibited by: IL4 and IL10 (from Th2)

• *Macrophage-Lymphocyte Interaction
• -Th cells release IFNg to stimulate MPs
• -MPs release IL1 and TNFa to stimulate Th cells

• -Secrete IL4, IL5, IL10, IL13
• -recruit eosinophils for parasite defense
• -promote IgE production by B cells
• -inhibited by: IFNg (from Th1)

• -help maintain immune tolerance by suppressing CD4 and CD8 T cell effector fxns
• -produce anti-inflammatory cytokines (IL10, TGFb)

• Express:
• -CD3
• -CD4
• -CD25 (alpha chain of IL2R)

• Direct killing (induce apoptosis):
• -virus infected cells
• -neoplastic cells
• -donor graft cells

• Release Cytotoxic Granules:
• -perforin (deliver contents into target cell)
• -granzyme (serine protease that activates apoptosis)
• -granulysin (antimicrobial, induces apoptosis)

Interacting proteins important in humoral immunity and inflammation

• Activation: 
• 1. Classic pathway - IgG or IgM mediated
•          "GM makes classic cars"
• 2. Alternative pathway - Spontaneous and microbial surface 
• 3. Lectin - microbiaal surfaces (e.g. mannose)
• 

• Functions:
• - C1, C2, C3, C4 - viral neutralization
• - C3b - opsonization (C3b binds bacteria)
• - C3a, C5a - anaphylaxis
• - C5a - neutrophil chemotaxis
• - C5b - 9 - cytolysis by MAC

• Opsonins:
• -C3b and IgG are the two primary opsonins in bacterial defense
• -C3b also helps clear immune complexes

• Inhibitors:
• -Decay accelerating factor (DAF) and C1
•         esterase inhibitor help prevent complement activation on self (e.g. RBC)

• C2 esterase inhibitor deficiency - Hereditary angioedema. ACE inhibitors are contraindicated
• C3 deficiency - severe, recurrent pyogenic sinus and respiratory tract infections; ↑ susceptibility to type III hypersensitivity reactions
• C5-C8 deficiencies - recurrent Neisseria bacteremia
• DAF(GPI anchored enzyme) - complement-mediated lysis of RBC and paroxysmal nocturnal hemoglobinuria (PNH)

Hot T-Bone stEAk

• -IL-1: fever (hot)
• -IL-2: stimulates T cells
• -IL-3: stimulates Bone marrow
• -IL-4: stimulates IgE production
• -IL-5: stimulates IgA production

-"clean up on aisle 8" - Neutrophils are recruited by IL-8 to clear infections

• IL-1 - endogenous pyrogen; causes fever, acute inflammation
• -activates endothelium to express adhesion molecules
• -induces chemokine secretion to recruit leukocytes

• IL-6 - endogenous pyrogen; causes fever
• -also secreted by Th cells
• -stimulates production of acute-phase proteins (reactants)

• IL-8 - Major chemotactic factor for neutrophils
• -"Clean up on aisle 8" neutrophils are recruited by IL-8 to clear infections

• IL-12 - Induces differentiation of T cells into Th₁ cells
• -activates NK cells
• -also secreted by B cells

• TNF-α - Mediates septic shock
• -Activates endothelium
• -leukocyte recruitment and vascular leak

• CD14
• CD40
• MHC I
• MHC II
• B7
• Fc and C3b receptors (enhanced phagocytosis)

• CD16 (binds Fc of IgG)
• CD56 (unique marker for NK)
• MHC I

• Passive
• -receiving preformed antibodies
• -onset is rapid
• -duration is only the span of the antibodies (half-life = 3 weeks)
• -IgA in breast milk, antitoxin, humanized monoclonal antibody

• Active
• -exposure to foreign antigens
• -Onset is slow
• -Duration is long-lasting (memory)
• -Natural infections, vaccines, toxoid

"After exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive) - To Be Healed Rapidly"

• Type I - Anaphylaxis and atopic
• Type II - Antibody mediated
• Type III - Immune complex
• Type IV - Delayed (T-cell-mediated) type

• ACID:
• -Anaphylactic and Atopic (type I)
• -Cytotoxic (antibody mediated) (type II)
• -Immune complex (type III)
• -Delayed (cell mediated) (type IV)

• Anaphylactic and atopic - free antigen cross-links IgE on presensitized mast cells and basophils, triggering release of vasoactive amines that act at postcapillary venules (i.e. histamine)
• -Reaction develops rapidly after antigen exposure due to preformed antibody

• First and Fast (anaphylaxis).
• -Types I, II, and III are all antibody mediated

Test: scratch test and radioimmunosorbent assays

Antibody mediated - IgM, IgG bind to fixed antigen on "enemy" cell, leading to lysis (by complement) or phagocytosis

"Cy-2-toxic" - Antibody and complement lead to membrane attack complex (MAC)

• Mechanisms:
• 1. Opsonize cell or activate complement
• 2. Antibodies recruit neutrophils and macrophages that incite tissue damage
• 3. Bind to normal cellular receptors and interfere with functioning

Test: direct and indirect Coombs' test

• Immune complex - antigen-antibody (IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes
• -Imagine immune complex has 3 things stuck together: antigen-antibody-complement

• Serum sickness - immune complex disease: antibodies to foreign proteins are produced (takes ~5 days)
• -immune complexes form and are deposited in membranes, where they fix complement (leads to tissue damage)
• -More common than Arthus reaction
• Presentation: fever, urticaria, arthralgias, proteinuria, lymphadenopathy 5-10 days post antigen exposure (most likely drug)

• Arthus reaction - local subacute antibody mediated reaction.
• -Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in skin
• -Edema, necrosis, activation of complement
• -Test: immunofluorescent staining

• Delayed (T-cell mediated) type - sensitized T lymphocytes encounter antigen and release lymphokines
• -leads to macrophage activation; no antibody involved

• 4th and last - delayed.
• -cell mediated; not transferable by serum
• 4 T's = T lymphocytes, Transplant rejections, TB skin tests, Touching (contact dermatitis)

• Test: patch test (i.e. PPD)
•