Lymphoid structure
Immune system organ
1→bone marrow:B cell, thymus: T cell
2→spleen, lymph node, tonsil(扁桃腺), peyer patch
lymph node
many afferent(求心路), 1 or more efferent(遠心路)
function : nonspecific filtration by macrophage, storage of B/T cell, immune response activation
follicle : Bcell, 1°follicle→dense and dormant(休止), 2°follicle→germinal center(胚中心), active
medulla: medullary cord(髄索), medullary sinus(髄洞): communicate with efferent and contain reticular cells(細網細胞) and macrophage
paracortex(傍皮質): T cell, between follicle and medulla, endothelial venules(内皮細静脈), enlarge in extreme cellular immune response
drainage(lymph node)
cervical : head and neck (upper respiratory tract infection; 上気道感染, infectious mononucleosis; 伝染性単核球症, Kawasaki disease
mediastinal(縦隔) : trachea and esophagus (1° lung cancer, granulomatous disease; 肉芽腫症)
hilar(肺門): lung (granulomatous disease)
axillary(腋窩) : upper limb, breast, skin above umbilicus (mastitis; 乳房炎)
celiac(腹腔): liver, stomach, spleen, pancreas, upper duodenum
superior mesenteric: lower duodenum, jejunum, ileum, colon to splenic flexure
inferior mesenteric : colon from splenic flexure to upper rectum
para-aortic : testes, ovaries, kidney, uterus
internal iliac(内腸骨) : lower rectum to anal canal, bladder, vagina, cervix, prostate (STI; 性感染症)
superficial inguinal(浅鼠径): anal canal, skin below umbilicus, scrotum(陰嚢), vulva(外陰部)
popliteal(膝窩) : dorsolateral foot, posterior calf(後ふくらはぎ)
right and upper zone of diaphragm: into junction of right subclavian and internal juglar vein
other go into thoracic duct and then go into junction of left subclavian and internal juglar vein
spleen
LUQ of abdomen, anterior to left kidney, protected by 9-11 ribs
sinusoid is long, vascular channel in red pulp(赤脾髄), fenestrated(有窓) basement membrane
T cell in periarteriolar lymphatic sheath(PALS) within white pulp
B cell in follicle
specialized B cell and macrophage, between red pulp and white pulp, where antigen presenting cell capture blood-bone antigen
dysfunction→↓IgM→↓C3b→↑susceptibility
postsplenectomy
Howell-Jolly body, Target cell, thrombocytosis, lymphocytosis
Thymus
anterosuperior mediastinum
Tcell differentiation and maturation
derived from third pharyngeal pouch
immature T cell in cortex
mature T cell and Hassall corpuscle(containing reticular cell) in medulla
sail-shaped in childhood
hypoplastic in DiGeorge and severe combined immunodeficiency(SCID)
thymoma: associated with myasthenia gravis(重症筋無力症)and SVC syndrome
Celllular component
innate vs adaptive
innate immunity
neutrophil, macrophage, monocyte, dendritic cell, NK cell, complement, physical epithelial barrier, secreted enzyme
germline encoded(生殖細胞にコード化されている)
persist through generation
non specific, rapid, no memory response
lysozyme, complement, C-active protein, defensis
TLR recognize pathogen-associated molecular patterns(PAMPs)→activation of NK-κB (example of PAMPs: LPS, flagellin, nucleic acid
adaptive immunity
T cell, B cell, circulating antibody
varidation through V(D)J recombination
specific, memory response is faster and more robust
immunoglobulin
memory cell
Major histocompatibility complex (MHC)
MHC1
HLA-A,B,C
TCR and CD8
1 long chain, 1 short chain
all nucleated cell, APCs, platelet (not on RBC)
endogenously synthesized antigen is presented
to CD8+ T cell
β2-microglobulin
MHC2
HLA-DP,DQ,DR
TCR and CD4
2 equal length chain
APCs
exogenously synthesized antigen is presented
to CD4+ T cell
subtypes associated with disease
A3 : hemochromatosis
B8 : addison disease, myasthenia gravis, Graves disease
B27 : Psoriatic arthritis(乾癬性関節炎), ankylosing spondylitis (強直性脊椎炎), IBD-associated arthritis, reactive arthritis
DQ2/DQ8 : Celiac disease
DR2 : multiple sclerosis, hay fever(枯草熱、花粉症による熱), SLE, Goodpasture syndrome
DR3 : diabetes type 1, SLE, Graves disease, Hashimoto thyroiditis, Addison disease
DR4 : Rheumatoid arthritis, diabetes mellitus type 1, Addison disease
DR5 : Hashimoto thyroiditis
natural killer cell (NK cell)
perforin and granzyme : induce apotosis of virally infected cells and tumor cells
enhanced by IL-2, IL-12, IFN-α, IFN-β
also have antibody-dependent cell-mediated cytotoxicity
T cell and B cell
function
B cell
humoral immunity (液性免疫)
recognize antigen, produce antibody
maintain immunologic memory
T cell
cell-mediated immunity(細胞性免疫)
CD4+ T cell help B cell make antibody and produce cytokines to recruit phagocyte and activate other leukocyte
CD8+ T cell directly kill virus-infected cell
type 4 hypersensitivity
differentiation of T cell
T cell precursor→CD4+CD8+Tcell
CD8+Tcell→cytotoxic T cell
CD4+ T cell→helper T cell→Th1(+ IL-12, IFN-γ; - IL-4, IL-10), 2(+IL-2, IL-4; - IFN-γ), 17(+ TGF-β, IL-6), Treg(+ TGF-β)
positive selection: thymic cortex, T cell capable of binding self MHC on cortical epithelial cells survive
negative selection: thymic medulla, T cell with high affinity for self antigen undergo apotosis or become regulatory T cell
loss of negative selection causes autoimmune polyendocrine syndrome-1
T cell subsets
Th1
secret: IFN-γ
activate macrophage and cytotoxic T cell
induced by: IFN-γ, IL-12
inhibited by: IL-4, IL-10
Th2
secret: IL-4, IL-5, IL-6, IL-10, IL-13
activate eosinophil, promote production of IgE
induced by: IL-2, IL-4
inhibited by: IFN-γ
Th17
secret: IL-17, IL-21, IL-22
immunity against extracellular microbes (through neutrophic inflammation)
induced by: TGF-β, IL-1, IL-6
inhibited by: IFN-γ, IL-4
Treg
TGF-β, IL-10, IL-35
prevent autoimmunity
induced by: TGF-β, IL-2
inhibited by: IL-6
Th1→IFNγ→↑monocyte and macrophage (CD40L and CD40)
Cytotoxic T cell
release cytotoxic granules (perforin, granzyme B)
CD8, MHC1
Regulatory T cell
suppressing CD4, CD8
expression of CD3,4,25 and FOXP3
IPEX (immuno dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome: deficiency of FOXP3→autoimmunity
activation
APCs: B cell, debdritic cell, Langerhans cell, macrophage
T-cell activation
dendritic cell migrate to draining lymph node→antigen on MHC2 is recognized by TCR on CD4+ cell , cross-presented on MHC1 to CD8+ cell→signal via interaction of B7 protein and CD28→activate
B cell activation
presented on MHC2 and recognized by TCR on Th cell→CD40 on B cell bind CD40L on Th cell→cytokine from Th cell determine Ig class→activate
Immune response
antibody structure
Y字
heavy chain (Fc and Fab), light chain (Fab)
Fab: fragment, antibody binding, determines idiotype
Fc: constant, carboxy terminal, complement binding, carbohydrate side chain, determine isotype
diversity
random recombination of VJ or V(D)J
random addition of nucleotide (terminal deoxynucleotidyl transferase)
random conbination of heavy chain and light chain
specificity
somatic hypermutation and affinity maturation
isotype switching
Isotype
naive B cell express IgM and IgD
IgG
most abundant
cross placenta
IgA
prevent attachment of bacteria and viruses to mucous membrane, does not fix complement
monomer or dimer
transcytosis
GI tract, secretion (tears, saliva, mucus)
IgM
1°response to antigen, pentamer with J chain
IgD
surface of B cell
IgE
bind mast cells and basophils
type1 hipersensitivity response
inflammatory mediators (eg, histamin)
immunity to parasite (by eosinophil)
lowest in serum
thymus-independent (no protein) vs thymus-dependent (protein)
Complement
Classic : IgG or IgM mediated : C1,C2→C2a,C2b C2b,C4b→C4b2b C3→C3a,C3b
Alternative : microbe surface molecule : C4→C4a,C4b C4b,C2b→C4b2b C3→C3b
Lectin : mannose or other sugar on microbe surface: C3→C3b C3b,Bb→C3bBb C3→C3b
続き: C5→C5b→membrane attack complex(MAC)
C3b: opsonization, C3a,C4a,C5a: anaphylaxy, C5a: neutrophil chemotaxis, C5b-9: cytolysis(細胞融解)
Opsonin: C3b and IgG, enhance phagocytosis
Inhibitor: prevent complement activation
disorder
early complement deficiency (C1-C4): recurrent pyogenic sinus (化膿性洞) and respiratory tracy infection, ↑risk of SLE
terminal complement disorder (C5-C9) : susceptibility to Neisseria
C1 esterase inhibitor deficiency : angioedema, ↓C4, ACE inhibitor is contraindicated
paroxysmal nocturnal hemoglobinuria; PNH; 発作性夜間ヘモグロビン尿症; defect in PIGA gene, anchors for complement inhibitor, lysis of RBC
cytokine
IL-1
fever, acute inflammation
IL-2
T cell
IL-3
bone marrow
IL-4
IgE, IgG, Th2
IL-5
IgA, eosinophil
IL-6
acute phase of protein production
IL-8
chemotactic(遊走) factor of neutrophil
IL-12
Th1, NK cell
TNF-α
activate endothelium, WBC recruitment, vascular leak, granulomas (TB), cachexia(悪液質)
IL-10
attenuate inflammatory response
Interferon-γ
secreted by NK cell and T cell (response to IL-12 and antigen), ↑macrophage kill activity, ↓Th2
Respiratory burst; 呼吸バースト(oxidative burst; 酸化バースト)
reactive oxigen species;ROS(活性酸素) : immune response
NADPH involves in creation and neutralization of ROS
O₂→O₂⁻→H₂O₂→HClO→kill bacteria
H₂O₂→H₂O (glutathione peroxidase)
patient with CGD ↑risk of catalase + species(neutralizing H₂O₂)
Interferon-α,β
against RNA, DNA virus
downregulating protein synthesis and upregulating MHC expression (in virus-infected cell)
Cell surface protein(まとめ)
T cell
TCR, CD3, CD28
CD4, CD40L, CXCR4/CCR5 (in helper T cell)
CD8 (cytotoxic T cell)
CD4,CD25 (regulatory T cell)
B cell
Ig, CD19,20,21,40, MHC 2, B7
macrophage
CD14, CD40, CCR5, MHC2, B7, Fc and C3b receptor
NK cell
CD16,56
hematopoetic stem cell
CD34
Anergy
state during which cell cannot become activated by exposure to antigen
without costimulatory signal, anergy occur
self tolerance
Vaccination
passive vs active immunity
active immunity
exposure to foreign antigen
slow onset
long-lasting protection
eg. natural infection, vaccination, toxoid
passive immunity
receiving preformed antibody
rapid onset
short span
eg. IgA in breast milk, maternal IgG crossing placenta, antitoxin, humanized monoclonal antibody
after exposure to toxin (rapid)
Live attenuated vaccine(弱毒生ワクチン)
lose pathogenicity but retain capacity for transient growth
cellular and humoral response
strong, lifelong
may revert to virulent form
eg. adenovirus, polio, varicella(水痘), small pox, BCG, yellow fever, influenza, MMR, Rota
killed or inactivated vaccine(不活化ワクチン)
inactive, maintain epitope structure
humoreal response
safer, but weaker
eg. rabies(狂犬病), influenza, polio, hepatitisA
subunit
only antigen that stimulate immune response
lower chance of adverse reaction
expensive, weaker
eg. HBV, HPV, acellular pertissis(百日咳), neisseria meningitidis, S.pneumoniae, H.influenzae type b
toxoid
denatured bacterial toxin with intact receptor binding site
protect against bacterial toxin
decrease with time
eg. C.tetani, C.diphtheriae
Hypersensitivity types
type1
anaphylactic and atopic
immediate: IgE→degranulation→release of histamine and tryptase
late: chemokine and cytokine from mast cell→inflammation and tissue damage
eg. Anaphylaxis
type2
antibody bind to cell-surface antigen→destruction, inflammation, and dysfunction
cellular destruction: opsonized→phagocytosis, activation of complement system, NK cell killing
inflammation: activation of complement system and Fc receptor mediated inflammation
cellular dysfunction: abnormal blockade or activation of downstream process
direct/ indirect Coombs test: detect antibody-RBC
eg. autoimmune-hemolytic anemia(AIHA), immune thrombocytopenia(血小板減少性紫斑病), transfusion reaction(輸血反応), hemolytic disase of newborn
eg. Goodpasture syndrome, Rheumatic fever, Hyperacute transplant rejection
eg. myathenia gravis, graves disease, pemphigus vulgaris(尋常性天疱瘡)
type3
antigen-antibody complex activate complement
vasculitis and systemic manifestation
Serum sickness
1-2 weeks later, complex form and deposit in tissue→inflammation and tissue damage
Artus reaction
intradermal injection→immune complex
edema, necrosis, activation of complement
eg. SLE, polyarteritis nodosa(結節性多発動脈炎) PSGN
type4
involving Tcell
CD8+ cell kill directly
inflammation by CD4+ cell
not involve antibody
eg. contact dermatitis, GVHD
PPD(ツ反)
delayed
blood transfusion reaction
allergic/anaphylactic reaction
type1
against plasma protein
urticaria8蕁麻疹), pruritus(掻痒), fever, wheezing, hypotension, shock
within minutes to 2-3 hours
febrile nonhemolytic transfusion reaction; FNHTR(発熱性非溶血性副作用)
type2
with host antibody against donor HLA and WBC
fever, headache, chill, flushing
within 1-6 hours
acute hemolytic transfusion reaction; AHTR(急性溶血性副作用)
type2
intravascular hemolysis (ABOなど) and extravascular hemolysis (host antibody against donor RBC)
transfusion-related acute lung injury; TRAIL(輸血関連急性肺障害)
donor antibody against recipient neutrophils and pulmonary endothelial cell
within 1 hour
within 6 hours
Immunodeficiencies
autoantibody
anti-ACh receptor---myathenia gravis
anti-presynaptic voltage-gated calcium channel---Lambert-Eaton myasthenic syndrome
anti β₂ glycoprotein---antiphospholipid syndrome
antinuclear(ANA)---nonspecific, SLE
anticardiolipin, lupus anticoagulant---SLE, antiphospholipid syndrome
anti-dsDNA, anti-Sm---SLE
Rheumatoid factor, anti-CCP---rheumatoid arthritis
anti-Ro/SSA, anti-La/SSB---Sjogren syndrome
anti-Scl-70---scleroderma
anticentromere---limited scleroderma (CREST syndrome)
antisynthetase, anti-SRP, anti-helicase---polymyositis(多発性筋炎), dermatomyositis
antimitochondrial 1° biliary cirrhoris---1° biliary cholangitis
anti-smooth muscle--- autoimmune hepatitis type1
MPO-ANCA/p-ANCA---microscopic polyangitis;MPA(顕微鏡的多発血管炎), eosinophilic granulomatosis with polyangitis;EGPA(好酸球性多発血管炎性肉芽腫症), ulcerative colitis(潰瘍性大腸炎)
PR3-ANCA/c-ANCA---granulomatosis with polyangitis; GPA(多発血管炎性肉芽腫症)
anti-phospholipaseA₂ receptor---1°MN
anti-hemidesmosome---bullous pemphigoid(類天疱瘡)
anti-desmoglein---pemphigus vulgaris(尋常性天疱瘡)
anti TSH receptor--- Graves disease
anti glutamic acid decarboxylase, islet cell cytoplasmic antibody---type 1 diabetes mellitus
anti-glomerular basement membrane---Goodpasture syndrome
X-linked agammaglobulinemia
defect in BTK→no B-cell maturation, XR
recurrent infection
absent lymph node and tonsil
Selective IgA deficiency
most common
asymptomatic
infection, autoimmune disease, atopy, anaphylaxis
↓IgA
common variable immunodeficiency
defect in B cell differentiation
thymic aplasia(DiGeorge syndrome)
22q11
failure to develop 3rd and 4th pharyngeal pouch→absent thymus and parathyroid
tetany, recurrent infection, conotruncal abnormalities
IL-12 receptor deficiency
↓Th1 response, AR
AD hyper-IgE syndrome(Job syndrome)
defect in Th17 (STAT3 mutation)
impaired recruitment of neutrophil
coarse face, cold staphylococcal abscesses, retaind primary teeth, ↑IgE, dermatologic problem
chronic mucocutaneous candidiasis
Tcell dysfunction
defect in IL-17 or IL-17 receptor
severe combined immunodeficiency(SCID)
defective IL-2R gamma chain, adenosine deaminase deficiency
recurrent infection
treatment : antimicrobial prophylaxis, bone marrow transplant
ataxia-telangiectasia(毛細血管拡張性運動失調症)
defect in ATM gene
AR
cerebellar defect8ataxia), spider angiomas, IgA deficiency
↑AFP, ↓IgA,IgG, IgE
hyper-IgM syndrome
defctive CD40L
class switching defect
XR
Wiskott-Aldrich syndrome
mutation in WASp
leukocyte and platelet unable to recognize actin cytoskeleton→defective antigen presentation
XR
thrombocytopenia(血小板減少症), Eczema(湿疹), Recurrent infection
leukocyte adhesion deficiency(白血球接着不全症)
defect in LFA-1 integrin(CD-18) on phagocyte
AR
recurrent infection, absent pus
Chediak-Higashi syndrome
lysosomal trafficking regulator gene(LYST)
microtubule dysfunction in phagosome-lysosome fusion
AR
progressive neurodegeneration, lymphohistiocytosis(血球貪食症候群), albinism, peripheral neuropathy, recurrent infection
chronic granulomatous disease
defect of NADPH oxidase
superoxide↓
X-linked
Infection
Bacteria
↓Tcell: sepsis
↓Bcell: P.aeruginosa(緑膿菌), S.pneumoniae(肺炎球菌), H.influenzae, N.meningitidis(髄膜炎菌), E.coli, Salmonella, K.pneumoniae, groupB streptococcus
↓granulocyte: complement
Viruses
↓T cell: CMV, EBV, JC virus, VZV, chronic infection
↓B cell: poliovirus, enteroviral encephalitis
Fungi/Parasite
↓T cell: Candida, PCP, Cryptococcus
↓B cell : GI giardiasis
↓granulocyte : candida, aspergillus, mucor
Transplant
Graft
autograft : from self
syngeneic graft (isograft) : from identical twin or clone
allograft : from nonidentical indivisual of same species
xenograft : from different species
rejection
hyperacute
within minutes
pre-existing antibody react to donor antigen(type2)
thrombosis of graft vessel→ischemia/necrosis
acute
weeks to months
CD8; and CD4+ cell react to donor MHC(type4)
humoral; antibody develop after transplant
vasculitis
prevent immunosuppressant
Chronic
months to years
CD4+ T cell respond to recipient APCs presenting donor peptide
type 2 and 4
proliferation of vascular smooth muscle, parenchymal atrophy(実質萎縮), interstitial fibrosis
eg. bronchiolitis obliterans(閉塞性細気管支炎), accelerated atherosclerosis, chronic graft nephropathy, vanishing bile duct syndrome
graft-versus-host disease; GVHD
grafted immunocompetent T cells proliferate in the immunocompromised host and reject host cells with foreign protein→severe organ dysfunction
type4
maculopapular rash, jaundice, diarrhea, hepatosplenomegaly
usually in bone marrow and liver
Immunosuppressants
cyclosporine
Calcineurin inhibitor; prevent IL-2 transcription
other use: psoriasis(乾癬), rheumatoid arthritis
toxicity: nephrotoxicity
tacrolimus(FK506)
Calcineurin inhibitor
similar to cyclosporine
sirolimus(rapamycin)
mTOR inhibitor; prevent response to IL-2
prophylaxis in Kidney transplant
pancytopenia(汎血球減少), not nephrotoxic
basiliximab
monoclonal antibody
prophylaxis in Kidney transplant
edema, hypertension, tremor
azathioprine
inhibit lymphocyte proliferation by blocking nucleotide synthesis
rheumatoid arthritis, Crohnn disease, glomerulonephritis
toxicity: pancytopenia
mycophenolate mofetil
inhibit IMP dehydrogenase, prevent purine synthesis
lupus nephritis
toxicity : GI upset, pancytopenia, hypertension, etc, less nephrotoxic, neurotoxic
glucocorticoid
inhibit NF-κB
↓Tcell,Bcell function
many autoimmune diorder
Cushing disease, osteoporosis, hyperglycemia, diabetes, amenorrhea(無月経), atrophy, peptic ulcer, psychosis, cataract, avascular necrosis(無血管壊死)
recombinant cytokine
erythropoietin(EPO)
epoetin alfa---anemia
colony stimulating factor
G-CSF,GM-CSF---leukopenia
thrombopoietin
romiplostim, elthrombopag---autoimmune thrombocytopenia
interleukin-2
aldesleukin---renal cell carcinoma, metastasis melanoma
interferon
IFN-α---chronic hepatitis C and B, renal cell carcinoma
IFN-β---multiple sclerosis
IFN-γ---chronic granulomatous disease
therapeutic antibody
alemtuzumab : CD52 : CLL, MS
bevacizumab : VEGF : colorectal cancer, renal cell carcinoma, non-small cell lung cancer
cetuximab : EGFR : stage4 colorectal cancer, head and neck cancer
rituximab : CD20 : non-Hodgkin lymphoma, CLL
trastuzumab : HER2 : breast cancer, gastric cancer
adalimumab, certolizumab, golimumab, infliximab : TNF-α : Inflammatory bowel disease;IBD, rheumatoid arthritis, ankylosing spondylitis(強直性脊椎炎), psoriasis(乾癬)
daclizumab : CD25 : multiple sclerosis
eculizmab : C5 : PNH
natalizumab : α4-integrin : multiple sclerosis, Crohn disease
ustekinumab : IL-12/23 : psoriasis psoriatic arthritis
abciximab : platelet glycoprotein Ⅱb/Ⅲa : percutaneous coronary intervention; PCI(経皮的冠動脈形成術)の後に使う
denosumab : RANKL : osteoporosis
digoxin immune Fab : digoxin : antidote for digoxin toxicity
omalizumab : IgE : asthma
palivizumab : RSV F protein : RSV prophylaxis for high risk infant