Chapter 14  Immunologic Tolerance

1. Immunologic tolerance
  --> immune system randomly generates a vast diversity of antigen specific receptors and some of these will be self-reactive,

       tolerance prevents reactivity against the body's own.

- Definition of IR and immune tolerance

- induction of immune tolerance

Topics: 1) mechanism by which various Ags inhibit immune response
           2) factors that determine the nature and magnitude of responses

Importance of the elimination of Ag itself:
       in self-regulation of the immune response
          1) products (antibody, cytokine) have a short lives
          2) they are secreted for a brief period
          3) effector cells (lymphocytes) are short-lived

2. Immune tolerance
  --> tolerance results from the interaction of Ags with Ag receptors on lymphocytes

Antigens: 1) tolerogens - induce tolerance
                  (ex) all self-antigens, some foreign antigens
                2) immunogens - generate immune response
                  (ex) some foreign antigens - depend on physicochemical form, dose, route of administration

Role of antigen:
          1) protein Ags; humoral and cell mediated
             polysaccharide/lipids; no cell mediated
          2) amount of Ags; high dose/repeated administration of small amounts of Antigen (inhibitory)
          3) methods of administration; (table 11-1)
                             subcutaneous/intradermal --> immunogenic
                             intravenous/oral --> unresponsive

General features:
          1) immunologically specific -- deletion/inactivation of Ag-specific T and B cells
          2) tolerance to self is learned/acquired
          3) immature lymphocyes are more susceptible
          4) mature lymphocytes are also susceptible under inadequate conditions
              -- immunization conditions

Mechanisms: 1) deletion -- cell death of immature lymphocytes interacted with Ags
                      2) anergy -- inactivation of lymphocytes

 Sites of immune tolerance;

   in generative lymphoid organs (central tolerance)

   in peripheral lymphoid organs (peripheral tolerance)

(A) T lymphocyte toleranc(Fig 10-5)
--> effective way for maintaining long-lived unresponsiveness
     (a) T helper cells are critical for cellular and humoral responses
     (b) low levels of Ags are sufficient to induce the tolerance

--> mechanisms: T cell anergy

   (1) clonal deletion; for self-reactive clones
                     - during maturation in the thymus
                     - most effective to protein Ags present in thymus
                     
   (2) clonal anergy; T cells recognize APC without the costimulators, and unresponsive to subsequent same Ag stimulation
                     - in peptide-MHC complex on synthetic lipid membrane
                       in chemically treated APC

                       in CTLA-4:B7 interaction
                     - administration of large doses of Ags in aqueous soln's without adjuvants      

- Role of costimulators in T cell anergy;

 - Induction of T cell anergy using transgenic mouse (Fig 11-5)

** Activation-induced cell death

Question: what is the mechanism for tolerance to self-polysaccharides and lipids ?

(B) B lymphocyte tolerance
- a potent tolerogen -> polysaccharides (not processed)

--> mechanisms:
   (1) clonal deletion; a minor role
                     - occur in B cells of bone marrow (IgM B cells)
                     - evidence;
                       transgenic mice of heavy and light chain genes specific H-2K(k) haplotype
                       --> other haplotype mice, produce anti-transgenic antibody
                       --> same haplotype mice, no anti-transgenic antibody and reduction of B cells
   (2) clonal anergy;
                    - by Ag-induced block in mIgs (=clonal abortion)
                    - by functional inactivation

                    - evidence;
                      a) treatment of anti-Ig antibody on immature and mature B cells
                          --> in immature B cells, endocytosed but not expressed
                          --> in mature B cells, endocytosed and expressed
                      b) transgenic mice with HEL/anti-HEL antibody
                          --> clonal anergy is short-lived and required the continuous exposure to Ag

 -- Mechanism; downregulation of receptors

                         changes of receptor specificity

 B cell tolerance in a transgenic mouse model (Fig 11-10)

(C) Suppressor(= Regulatory) T lymphocyte tolerance
How was the suppressor T cells demonstrated ? (Fig 11-3)
 --> suppressive dose: high dose of aqueous Ag administration intravenously
 --> Thy-1 lymphocytes

Roles; 1) prevent immune response to self-Ag
          2) inhibit immune response to foreign Ags

-- action mechanism of regulatory T cells

General features;
  1. induced by same conditions that induce clonal anergy
     -- high dose of protein Ags, hapten w/o adjuvant, intravenous administration  
     -- direct interaction with Ags w/o MHC and APC  
  2. CD4 positive, high level of IL-2R α chain, FoxP3 required
  3. Ag-specific (?)
  4. MHC role in the development of suppressor T cells is unclear
  5. mediated by secreted proteins
     -- active secreted form of TCR

Problems;
  1. purification of the cells
  2. establishment of stable cell lines or hybridomas

Inhibitory mechanism;
  1. produce an excess of cytokines with inhibitory function                                
      --> TGF-β, IFN-γ , IL-10
  2. absorb necessary growth factors
      --> IL-2
  3. by secreted TCR

Chapter 12   Cytokines

A. General features

① produced by innate and adaptive immunity (Fig 12-1)
② secreted for a brief time; unstable
③ produced by diverse cell types
④ pleiotropism (Fig 12-2)                             
⑤ redundancy (Fig 12-2)
⑥ influence on the synthesis and action of other cytokines
⑦ autocrine, paracrine, endocrine
⑧ receptor expression; regulated by other cytokines and cyokine-receptor binding
⑨ cellular responses are slow
⑩ growth factors

B. Cytokines

(1) type I-IFN (α, β-IFN); same receptor and cellular responses

  ① α-IFN (leukocyte interferon)
     --> 20 related, family
     --> mononuclear phagocytes
  ②  β-IFN (fibroblast interferon)
     --> a single gene
     --> fibroblast

   functions
    --> inhibition of viral replication
    -->      "    of cell proliferation (ex: Trp synthesis)
    --> activation of NK cells
    --> MHC I (increase); lysis by CTL, MHC II (decrease)

(2) type II-IFN (γ-IFN)
   --> homodimeric
   --> sources: T cells, NK cells in T cell deficient animals
   --> enhanced by IL-2

  functions
    --> anti-viral activity
    --> activation of  phagocytes, neutrophils, NK cells
    --> MHC I and II (increase)                                                                      

(3) TNF
  --> host defense against gram(-) bacteria
  --> sources: LPS-phagocytes, Ag stimulated T and NK cells
        γ-IFN has an additive effect
  --> type II protein
  --> TNF receptor is present on most of cells

  functions;
   --> inflammation; 1) activation of inflammatory leukocytes, phagocytes
                               2) VED adhesive for leukocytes; by release of chemokines
   --> anti-viral effect
   --> fever induced
   --> acute phase response (hepatocytes)
   --> suppression of BM stem cell division (immunodeficiency)
   --> cachexia; by long-administration
                 wasting of muscle and fat cells

Fig 12-5

  lethal effects (at high concentration)
    1) reduction of tissue perfusion (by anti-myocardial contractility)
    2) increase of blood pressure; by thrombosis
    3) metabolic disturbance; glucose decrease in liver due to the overuse of glucose in muscle                                     

  Signaling by TNF receptors (Box 12-1)

    1) signaling intermediates (TRAF, RIP) ---> AP-1 and NF-kB

    2) FADD (Fas associated death domain) ---> caspase-8 ---> apoptosis   

** TRADD(TNF receptor-associated death domain), RIP(receptot interacting protein), TRAF(TNF receptor-associated  factor)                      

(4) Lymphotoxin (TNF-β)
   --> 30% homology, but same receptor
   --> sources: only activated T cells
   
(5) IL-1
   --> sources: activated phagocytes
        difference (with TNF); made by many diverse cell types
    --> 2 kinds (IL-1α, IL-1β)
           1) less homology (30%<)
            2) same receptor (in most cells, IL-1β is higher),
                             biological actions are identical

  functions;
    --> stimulation of B and T cell's growth
    --> inflammatory response
    --> compared to TNF
        1) similarity; fever, acute phase response, cachexia
        2) difference; not lethal, no increase of MHC expression

(6) IL-2
  --> T cell growth factor
  --> sources; activated CD4⁺ T cells

  functions;
     --> autocrine growth factors for B and T cells
     --> stimulation of NK cells
     --> IL-2R (p55 + p75)
          p55 (IL-2Rα) < p75 (IL-2Rβ) < p55 + p75

          p55 (IL-2Rα) is induced after T cell activation (Fig 11-11)

(7) IL-4
   --> sources; CD4+ T cells

  functions; (Fig 11-13)
     --> B cell and mast cell growth factor
     --> IgE switching
     --> increase of CD23 (FcR of IgE)

     --> stimulation of Th2 type T cells

     --> inhibition of macrophage activation

       **  Th1 and Th2 type cells

(8) IL-7
   --> sources; BM stromal cells

  functions;
    --> committed to the B lineage cells and maturation of CD4/CD8 negative T cells

    --> IL-7R; contains γchain of IL-2R

    --> growth factor for mature T cells, in vitro

(9) IL-6
   --> sources; phagocytes infected with gram(-) bacteria or IL-1 treated

                     vascular endothelial cells, fibroblast

   functions;
      --> acute phase responses
      --> B cell growth factor (in late stage)
      --> hybridoma, myeloma cell growth factor

(10) IL-12

       --> stimulates  γ-IFN production by NK and T cells

      --> stimulation of CD4+ helper T cells into Th1 producing γ-IFN

      --> activation of NK and CTL

Summary: Table 11-3 and Table 11-4

table 11-3

table 11-4

cytokine receptors and signaling

      --> based on structural homologies of extracellular cytokine-binding domain

      --> 5 families (Fig 11-3A)

     --> signaling (in type I and II cytokine receptors); Box 11-1

--> other signalings (Table 11-2)

Chemokines

leukocyte의 이동 (chemokinesis)을 촉진하는 cytokine들과 유사한 생리활성 물질을 지칭한다. 일반적으로 분자량이 8 - 10 KDa 정도의 크기로 대단히 작다. 이러한 chemokine들은 다시 크게 두가지 형태의 superfamily로 나누어 진다.
첫째는 CC chemokine 이며, 둘째는 CXC chemokine이다. 이들의 생리적 기능과 대표적인 chemokine들을 살펴보면 다음과 같다.

(Box 12-2); leukocyte recruitment

 ---------CXC---------------C----------------C--------------

----------CC-----------------C----------------C-------------- 

** chemokines

* IL-8
- 99 Aa -> 20 Aa signal seq. -> 79 Aa -> 72 or 77 Aa
  ; depend on cell types and culture conditions
  ; by N-terminal processing
- activity: N-terminal domain Glu-Leu-Arg (ELR)

  ______________________________________________________________________
   AVLPRSAK ELR C                             20%
          SAK ELR C                                 100%
             K ELR C                                   300%
                ELR C                                    300%
                  LR C                                        3%
                   R C                                      0.1%
  _______________________________________________________________________

- biological activities;
   1) shape change -- contractile cytoskeleton, actin polymerization
   2) exocytosis -- release of enzymes and other proteins
   3) receptor for adhesion -- upregulation
   4) bioactive lipids -- leukotriene

- IL-8 receptor (7 TM protein) (Fig 11-6)
   1) 2 types; IL-8R1 --> for CXC chemokines and IL-8
                     IL-8RII --> for IL-8
   2) G protein coupled; B. pertussis treatment
   3) desensitization; at high conc, by Ser/Thr phosphorylation --> binding to the arrestin

Cytokines in hematopoiesis

 Chapter 12   Complement (Effector mechanisms of humoral immunity)

-- Several biological functions of antibodies

(1) Neutralization function of antibodies

(2) opsonization function of antibodies

(3) antibody-dependent cell-mediated cytotoxicity (ADCC)

Complement system

- discovery: serum with anti-bacteria Ab

                                 ↓ heat (at 56 deg)

                 inhibit the lysis of bacteria

                                 ↓
               suggestion of another heat-labile component

A. biological functions
 1) cytolysis; pore-forming
 2) opsonization; opsonin
 3) inflammation; some complement -> chemotactic
 4) immune complex; clearance, solubilization                                              

B. pathways
 1) classical pathway; circulation - inactive form
                      activation - by Ag-Ab complex
 2) alternative pathway; activation - by binding to the surface of infectious organism

MASP (mannose-associated serine protease)

Classical pathway

(1) stringent conditions
   ① C1 activation - CH3 (IgM), CH2 (IgG)
                              IgM > IgG, aggregate
   ② only Ag-Ab complex, not free Ab  

(2) Ab-independent activation
   ① retrovirus, mycoplasma surface itself
   ② polyanionic molecules; DNA, heparin, chondroitin sulfate

(3) components

  C1; complex (c1q + c1r(2) + C1s(2))    (Fig 14-9)
      --> C1q binds to Ig
              6 chains (3 different)
              C-terminal; globular form
      --> C1s and C1r binding
              both are single chain
              C1s-C1r-C1r-C1s/c1q

                  C1q binding to Ig

           activation of associated C1r

                                  ↘  57KDa

                 C1r (28KDa)

                             ↘  57KDa

                 C1s (28KDa)

                   C4 + C2         * C4: 3 chains ( α, β, γ),  αchain has a thioester bond (Cys-Glu)    
                                                 
                          ↘ C4a
                          
                     C4b (nucleophilic attack)                                        

                         
                   metastable C4b

                    ↙           ↘

         water             surface proteins (amide)
                    ↓                carbohydrates (ester)                            

           iC4b                        ↓
   
                                    attach to the cell surface

         
                                 C2

                                 
                               C4b.2
                                             ↙C1s

                  C2b ↙    
                                  C2a

                                   
                              C4b.2a (C3 convertase)

                                               ↙  C3: α, βchain    
                                                              
                C3a  ↙       

                                C3b : α, βchain

                                    
                             C4b.2a.3b (C5 convertase)

                                                ↙ C5
                                    

               C5a    ↙     
                             C4b.2a.3b.5b

                                     
                             C4b.2a.3b.5b.6

                                      
                             C4b.2a.3b.5b.6.7

                                      
                            C4b.2a.3b.5b.6.7.8

                                      
                        C4b.2a.3b.5b.6.7.8.9 (MAC)     * MAC;    1 (C5-8) + 12-15 (C9)     (Fig 14-11)
                                                                         reorientation of lipid arrangement
                                                                         passive Ca²⁺ influx

Regulation of MAC (Fig 14-16)

                                                                         
(1) HRF (homologous restriction factor), CD59
   1) HRF; interfere C9 binding
   2) CD59;  "         C9 binding  
   -- restriction: same species
      protecting normal bystander cells from lysis
 (2) Vitronectin (= S protein)  
   --> interfere 5b.6.7 binding to lipid memb.
 

Biosynthesis
 --> hepatocyte and phagocyte                                                                                           

Alternative pathway  (Fig 14-6)
1. in the absence of antibody
2. not autologous cells, but on the surface of microbe
3. involved proteins; factor B, D, H, I, properdin, C3   (table 14-3)

                           C3b

                                     ↙ factor B

                             
                         C3b.B

                                     ↙ factor D (serine protease)
             Ba  ↙           
                              Bb

                              
                         C3b.Bb (= C3 convertase) 

                                 ↙ properdin (4 identical subunits, non-covalent)

                        C3b.Bb (stable form)

                              
                    C3           C3b           C3b.Bb.3b (= C5 convertase)

                                 ↘ C3a                          

Regulation of complement pathway  (Table 14-4)

(1) classical pathway

  ① C1 inhibitor (C1INH)
       serpin (serine protease inhibitor) family
       blocking of C1r and C1s cleavage (by stable formation)
       ** mechanism; using bait seq. (mimic seq. of substrate)
           - C1INH + C1r or C1s -> covalent ester linkage -> block of enzyme  activity
             prohibit the spontaneous activation of C1

  ② C4bp, DAF(decay accelerating factor), CR1
       inhibit C3 and C5 convertase formation
       structurally homologous
       RCA(regulators of complement activity) family
       binding to C4b (C4bp)

       displacement of 2a from C4b2a, Bb from C3bBb

   ③ factor I
       a serine protease
       cleavage of C4b;  ** cofactors -- CR1, C4bp, MCP(membrane cofactor protein)
                                                --> lack in the infectious microbes

         C4c (fluid)   +    C4d (memb.)

(2) alternative pathway

   ① factor H
       inhibit the binding between C3b and Factor B

       displacement of Bb from C3bBb

   ② factor I  (Fig 14-15)
       cleave the C3b                       ** cofactors -- CR1, C4bp, MCP(membrane cofactor protein)

                                
                         iC3b              3KDa frag.

          factor I            
                         C3dg              C3c (soluble)

  plasmin, trypsin       

                         C3d               C3g (soluble)                                                    

Complement receptor  

  table 14-6

(1) type I (CR1, C3b receptor, CD35)
  -- for C3b and C4b
  -- SCR (short consensus repeat); total 32 개
        60 - 70 Aas
        binding sites are in the second SCR of each group (7)
        ex; C4bp, CR2, DAF, MCP
  -- functions;
      1) inhibit C3 convertase activity
      2) opsonin receptor in phagocytes  (Fig 14-17)
  

(2) type II (CR2, C3d receptor, CD21)
   -- for iC3b and C3dg
      for  α-IFN and EBV

   -- functions;

       1) B cell activation

       2) trapping Ag-Ab complex in germinal centers

(3) type III (MAC-1, CR3, CD11bCD18)
   -- for iC3b
   -- integrin family
   -- carbohydrate binding capacity

   -- functions;

       1) phagocytosis

       2) leukocyte adhesion

(4) type IV (CR4, CD11cCD18)
   -- for iC3b
   -- integrin family

   -- functions;

       1) phagocytosis

       2) leukocyte adhesion

 Chap 15. Immunity to microbes  (Ref; Immunology, Roitt et al.)

(1) Immunity to viruses

A. defense mechanisms
 1) integrity of body surfaces
 2) specific anti-viral mechanism (Mx gene - inhibit influenza transcription)
 3)  γ-IFN -- by increase MHC I and II or activation of NK, macrophage
              ** 2'5' oligoadenylate synthetase / protein kinase (Fig 16-4)           

 4) antibody -- neutralization
 5) T cell immunity -- ① CD4 T cells  ② CD8 T cells

B. evading mechanisms                                                                                                                            
 1) antigenic variation -- ① antigenic drift (slight)    ② antigenic shift (radically)
 2) glycoprotein -- inhibit complement activation
 3) release short stretch of RNA -- interfere  γ-IFN action by competition on protein kinases
 4) inhibition of MHC I transport;  inhibition of antigen presentation -- at several stages (Box 15-3)

5) release of homologous cytokine receptors or cytokines

C. Influenza virus (Fig 16-9)

 - A, B, C type
 - hemagglutinin (HA) - 11 종   neuraminidase (NM) - 8 종
 - 면역형/보유동물/분리된장소/분리된달/년도(HA,NM)
   ex: A/swine/New Jersey/8/76 (H1N1)                                                                                                

(2) Immunity to bacteria

A. defense mechanisms
 - depend on the structure of invading bacterias
    ① gram-negative -- complement, cytotoxic cells (NK, Tc, phagocytes)
    ② gram-positive / mycobacteria / spirochaeta -- phagocytes
 1) surface;
    fatty acids in the skin --> anti-bacterial
    low pH in the stomach
    commensal bacterias --> colicin (anti-bacterial proteins)
 2) complement activation
 3) antibody
    block attachment and to pick up the useful molecules
    stimulation of complement activation
    neutralization

** for extracellular microbe

** for intracellular microbe

B. evading mechanisms (complement)
 1) by outer capsule itself --> prevent complement activation
 2) by membrane-bound enzymes --> degrade the fixed complements
 3) by secretion of decoy proteins --> deposit of complement on decoy proteins

C. killing mechanism of phagocytes
 1) O₂-dependent: (Fig 17-8)

    a) peroxidase independent; enzymes on the membrane of phagosome --> reduce O₂ --> oxygen intermediates
    b) peroxidase of phagocytes; additional toxic oxidants
    c) nitric oxide dependent; TNF/ γ-IFN --> NOS --> NO  (Fig 17-9)

 2) O₂-independent:
    cationic peptides --> ion-permeable channels
    lysosomal enzymes
    lactoferrin --> binding of Fe²⁺

D. evading mechanisms (phagocytes)
 1) secrete toxins --> inhibit chemotaxis
 2) capsules itself --> inhibit attachment of phagocytes
 3) catalase --> breakdown H₂O₂
 4) inhibit the  γ-IFN binding to the phagocytes

(3) Immunity to Fungi

A. defense mechanisms
 - by cell-mediated immunity
 1) T_H --> cytokines --> macrophages --> kill
 2) neutrophil; in respiratory mycoses
 3) defensin; a cationic protein, by formation of ion-permeable channels
 4) nitric oxide

(4) Immunity to protozoa and worms
 - tsetse fly; trypanosomes --> sleeping sickness / mosquitoes; plasmodium --> malaria

A. Features of parasite infections
   ① large --> a great variety and quantity of Ags
   ② complicate life history
   ③ host specificity
   ④ infections are chronic

B. defense mechanisms
   1) macrophages, neutrophil, eosinophil, platelets
   2) T_H and T_C
   3) antibody; complement activation/inhibition of attachment/ADCC/enhancement of phagocytosis

C. evading mechanisms
 1) outer surface --> inhibit the lysosomal enzyme activity
                      downregulate MHC II expression in macrophages
                      a scavenger of oxygen metabolites
 2) surface glycoprotein --> resemble the DAF(decay accelerating factor) --> inhibit the complement activation
 3) antigenic variation; malaria, sleeping disease (Fig 15-5)

 4) a thick extracellular cuticle; schistosome
 5) inhibit the attraction of neutrophil; an elastase inhibitor/tapeworm
 6) destruction of Ig; by proteases

(5) vaccination

A. Ags used in vaccines (table 15-6)

   ① living organisms/killed organisms; attenuated form
                       (ex) BCG -- 13 yrs culture of M. tuberculosis

                              cholera
                              yellow fever
   ② attenuated form; polio, rabies
   ③ subcellular fragments (surface antigens); safe and effective
                        (ex) 수막염, 임질, 간염
   ④ toxoids; most successful bacterial vaccines            
                         (ex) 파상풍, 디프테리아
   ⑤ recombinant DNA; for small antigens

B. reason for better vaccine using live organisms
  - greater number of microbial antigens
  - T cell dependency
  - MHC restriction

C. vaccine safety
  - contamination with unwanted proteins
  - not killed
  - reversion to wild type

D. difficulty to use vaccine for parasite and worms                       
  - polymorphic
  - antigenic variation
  - complicate life cycle --> different vaccines are required
                           
                                                                                                                                                           

Chapter 17  Tumor Immunology

Tumor antigens

 종양(tumor)은 self tissue에서 유래되어지며 중요한 특징으로써 정상세포는 생성된 후 일정시기의 수명을 거친후 죽음을 맞이하나 종양세포의 경우는 무한히 증식이 가능하다는 점이다. 이러한 종양세포는 정상세포와 비교하여 여러 차이점을 보여 주는데 대표적인 예로써 정상세포와는 다른 몇몇 단백질들을 세포막에 보유하고 있어서 숙주(host)인 우리몸의 면역계가 이를 bacteria 또는 virus 같은 병원균들과 동일시 하여 즉 foreign antigen으로 인식하고 면역반응을 수행하여 종양으로의 발전을 억제하는 것으로 생각하고 있다. 이러한 개념을 immunosurveilance 라 일컫는다.

Tumor antigen이란 상기의 언급한 종양세포에 특이적으로 발현되어지는 막단백질과 같은 항원들을 지칭하며 거의 대부분은 대응하는 정상세포들의 비정상적 변이(mutation) 또는 정상적인 단백질이라도 종양세포에서의 발현조절 이상으로 말미암아 비정상적 발현이 되기 때문에 나타나는 것이다. 이러한 tumor antigen은 virus의 단백질에 의해서도 야기 되어질 수 있으며 나아가 이러한 유발요인들은 비단백질 성분인 탄수화물 이나 지질의 비정상적인 생성을 유도하여 이러한 물질들도 tumor antigen으로써의 역할을 하게끔 하고 있다. Tumor antigen들의 발현자체 또한 대응하는 정상세포와 다를뿐 만 아니라 종양세포들간에도 상당한 차이점을 보여주고 있다.

종류; table17-1

    (1) products of mutated oncogenes and tumor suppressor genes

    (2) products of other mutated genes

    (3) overexpressed and abnormally expressed cellular proteins

    (4) tumor antigens encoded by genomes of oncogenic viruses

    (5) oncofetal antigens

    (6) altered glycoprotein and glycolipid

    (7) tissue-specific differentiation antigens

    Tumor antigen을 발현의 형태에 따라 분류하여 보면 다음과 같다.

 1) tumor-specific antigens (TSA)
    오직 종양세포에만 특이적으로 발현되며 정상세포에는 발현 되어지지 않는다. 그러므로 숙주에 의한 강력한 면역반응을 야기시킨다.
 2) tumor-associated antigens (TAA)
    종양세포뿐만 아니라 대응하는 정상세포들에서도 발현되어지며 따라서 숙주에 의한   면역반응을 야기시킬 수도 있으나 종종 숙주로 부터 self-antigen으로 인식되어 self-tolerance기작을 통하여 면역반응 자체로부터 회피할 수 있다.

Immunologic effectors    

(1) T lymphocytes
- CTL (cytotoxic T lymphocytes)를 통한 암세포의 제거는 효율성이 높다
- tumor-specific CTL; 이미 종양세포를 보유하고 있는 동물이나 사람들에서부터 동정할 수 있다
- TIL(tumor-infiltrating lymphocytes); CTL을 함유
- CD4⁺ T helper cells; 많은 종류의 cytokine들에 의하여 CTL development에 영향을 미치어 간접적으로는 항암작용에 분명히 연관되어 있다
   TNF (tumor necrosis factor),  γ-IFN를 생성분비 -> class I MHC molecules 발현을 증대

(2) Natural Killer Cells
- Natural killer 세포는 CTL에 의한 종양세포의 사멸기작과 매우 유사
- 종양세포들에 대한 특이성에 있어서 상당히 광범위한 점
- MHC molecules의 수가 적을수록 natural killer 세포의 좋은 표적물
- LAK cells; lymphokine-activated killer cells (IL-2)

(3) Macrophages
- Macrophage; NK 세포와 마찬가지로 Fc  receptor를 보유, 항체를 매개체로 종양세포를 사멸시킬 수 있다

                      (lysosomal enzymes, reactive oxygen metabolite등의 방출)
- TNF; 종양세포의 TNF receptor를 통한 세포의 사멸작용, cytoskeletal  proteins의 파괴, gap junction형성의 방해 (직접

  적)  thrombosis 를 야기함 (간접적)

(4) Antibodies
- 항암효과는 상당히 떨어진다
- complement activation, ADCC (antibody dependent cell-mediated cytotoxicity)기작을 이용하여 간접적으로 macrophage, NK 세포를 통한 항암작용

Tumor escape

① 종양세포들은 CTL의 주표적이 되는 MHC class I을 자체적으로 감소
② 대부분의 종양세포들은 MHC class II을 가지지 않음
③ 어떠한 종양세포들은 costimulator (예를들어 B7)를 발현시키지 않음
④ 종양세포 자체는 anti-tumor immune response를 억제할 수 있는 물질을 생성; (TGF-β)
⑤ 종양세포들은 항원의 형태를 tolerogenic form로 표현
⑥ antigenic modulation
⑦ 종양세포들은 일반적으로 유전자 불안정성; MHC에 변이가 일어나 MHC의 고유기능인 antigen presentation 기능을 하지 못함
⑧ antigen masking; 세포벽의 glycocalyx molecules에 의한 것                     

Tumor immunotherapy

Active tumor immunotherapy
host의 면역반응을 증대시킴으로써 궁극적으로 종양세포를 치료하는 개념이다.

(1) nonspecific stimulation
- 크게 3가지 정도의 방법이 이용되고 있다.
  ① BCG 투여방법; macrophages를 활성화, 실제로 방광암 이나 피부암환자
  ② 적은양의 CD3 항체를 투입; T 세포의 polyclonal activation을 유도
  ③ cytokines의 투여; 숙주의 면역시스템을 증대

(2) vaccination
- 대부분에 있어서는 성공적인 결과를 얻지 못하였다
- tumor-specific antigen의 유전자를 클로닝하여 암환자에 투여하는 방법

(3) costimulator 및 cytokines 처리
- cytokines을 투입하여 전반적으로 숙주 (즉 암환자) 의 면역시스템을 강화
- 결핍된 costimulator (예로써 B7 molecule)의 유전자를 transfection시킴

Passive tumor Immunotherapy
외부적으로 immune effector들을 암환자와 같은 치료가 필요한 환자에 주입하여 치료하는 방법을 말하는 것이다

(1) adoptive cellular therapy
  - 인위적으로 배양한 면역세포들을 암환자에 투입

1-A. LAK cell therapy
  - 암환자의 peripheral blood leukocytes를 분리
  - 인위적으로 고농도의 IL-2를 넣어서 배양한 다음 LAK 세포를 만들고
  - 다시 환자에 주입하여 치료

1-B. TIL therapy
  - 근거는 TIL에 항암작용에 중요한 면역세포들인 NK 세포 와 CTL이 함유
  - 오직 일부분 세포들이 항암작용에서 그 기능을 수행하는 것
  - TNF와 같은 뛰어난 항암효과를 가진 cytokine의 전달수단으로 이용

(2) therapy with anti-tumor antibody
- 하나의 목표물(종양세포)에 공격무기(toxic agents)를 전달하는 하나의 수단
- 공격무기는 ricin, diphtheria toxin; 강력한 단백질 생성 억제제
- Immunotoxin; ① toxicity의 상실이 없어야 하며
                       ② target에 대한 특이성
                       ③ systemic effects (hepatotoxicity, vascular leak syndrome)이 없어야함

Chapter 20   Congenital and aquired immunodeficiencies

(1) B cell immunodeficiency
   - defective in Ab production
   - recurrent infections with pyogenic microorganism (pneumococcus, streptococcus)   

                 "               intestinal parasites
                "               virus (polio)
                              
(2) T cell immunodeficiency
    combined immunodeficiency
  - SCID; ① adenosine deaminase (ADA) --> block DNA synthesis, transmethylation
          ② purine nucleoside phosphorylase (PNP)
          ③ MHC II
          ④ IL-2R γchain (IL-2, IL-4, IL-7)
          ⑤ RAG-1 and RAG-2

(3) Defects in lymphocyte activation

   - 장소

- 종류

(4) Wiskott-Aldrich syndrome
   - eczema (습진), reduction of platelets
   - decrease in T cells
   - no Ab production response to LPS
   - susceptible to pyogenic bacterias
   - lymphocyte number is normal

   - short arm of X-chromosome linked disease
   - defective in glycosylation of membrane proteins

(5) Ataxia-telangiectasia
   - frequent cancer with advancing age
   - effect on both B and T cells (decreased T cells, normal B cells)
   - translocation in Ig or TCR loci
   - defective in DNA repair

 Acquired Immunodeficiency

 - 종류

 - HIV life cycle;

 - entry mechanism;

- How HIV is progressed into disease ?