Phase 1

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Innate Immunity

Complement pathway

1. Classical: Antigen-antibody complex C1qrs, C4, C2

2. MB-Lectin: Mannose on pathogen MBL, MASP, C4, C2

3. Alternative: Pathogen C3, B, D 

C3 convertase: C4a, C3a, C5a: Recruitment phagocytosis

C3b: Opsonisation
C5b, C6,7,8,9: Lysis 
 

Gram negative: Lipopolysaccharide (2 phospholipid membrane, inner peptidoglycan)
Gram positive: Lipoteichoic acid (outer peptidoglycan and inner cytoplasmic membrane)

TLR 1/2/6: Peptidoglycan, Lipoprotein, Lipoarabinomanannan (mycobacteria), GPI (T.cruzi), Zymosan (yeast)
TLR 3: dsRNA (viral)
TLR 4: LPS (Gram negative)
TLR 5: Flagellin
TLR 9: Unmethylated CpG DNA

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Innate Immunity

NOD 1: y-glutamyl diaminopimelic acid (PGN negative)
NOD 2: muramyl dipeptide (PGN)

Neutrophils: O2 burst (reduced by NADPH oxidase to form hydroxyl radicals): H2O2 + Cl. = OCl. + H2O 
OCl.+H2O= O2+Cl.+H2O/ 2O2. + 2H+=H2O2 + O2 SOD/ H2O2= H2O + O2  

Macrophages: INFy+TNFa= O2+ Arg= NO synthetase= NO + Citrulline (+ Tetrahydrobiopterin)

IL-1/6: Inflammation, fever

TNFa: Fever, macrophage

IL-12: CD4 T cell differentiation

IL-8: macrophage, endothelial cells

MCP: monocyte chemotactic protein  

IFNa/IFNb: Natural Killer: TNFa/IL-12--> IFNy--> Macrophages and /CD4+ Th1 cells 

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Adaptive Immunity

Ig heavy chain gene rearrangement: VDJ - Also T cell Receptor beta and delta

Ig light chain gene arrangement: VJ - Also T cell Receptor alpha and gamma

Junctional Region Diversity: TdT adding random nucleotides

B cell this happens- Bone marrow

T cells- Thymus

B cells ONLY

Hypermutation and affinity maturation- germinal centre of B cell folicles (tonsil, spleen) dark zone

Class switching

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Adaptive Immunity

IgG (1/2 etc) In blood after class switching- opsonisation- antibody-dependent cellular cytotoxicity

IgE Mast cell and degranulation/ parasitic 

IgA Mucosal antibody (B cells at surfaces and in breast milk) - form protective dimer

IgM Pentamers (too large to pass into tissues and cross placenta)

IgD Naive B cells (membrane-bound)

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T cells effector and function

MHC 1: a1/a2/a3/b2m - endogenously expressed on nucleated cells CD8+

MHC 2: a1/a1/b1/b2 - aB hetrodimer expressed on antigen presenting cells CD4+

Class 2, 3, 1 on short arm of chromosome 6 in co-dominant manner 

T cell receptor: a (Va/Ja/Ca) b (Vb/Db/Jb/Cb)

4.5 x 10^9 TCR possible 

Costimulation- CD28/86 

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T cells effector and function

Th1

IL-12--> Th1--> IFNy/IL-2 

Intracellular pathogens (Listeria, TB, Leprosy)

IFNy--> macrophages

IL-2/IFNy--> CD8+ T cell

Th2

IL-4--> Th2--> IL4/5/13/2

Extracellular parasites (Schistosoma, Tricinella)

Division, Class switching, Affinity maturation, differentiation

Th17

TGFb/IL-6--> Th17--> IL-17/22

Extracellular bacteria (Klebsiella pneumoniae, candida albicans) 

Neutrophil, epithelium/fibroblasts

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T cells effector and function

TReg

TGF-b + IL-2--> Treg--> TGFb/ IL-10 

Suppress activity of APC, proliferation of responder, cytokines, antibody, NKT/NK

nReg: naturally occurring (in thymus)- self antigens/ autoimmunity
Lack of: IPEX  

aTreg: adaptive (periphery)- autoimmunity

T cells derive from bone marrow precursors and develop in thymus

Thymic education: Positive selection for MHC in thymic cortex

Negative selection to eliminate high affinity self-reactive T cells in thymic medullary epithelial cells

Activation of naive lymphocytes occurs in lymphoid organs 

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Immunological Memory

Bone marrow--> Tm --> High frequency, avidity and immediate effector function

LN--> Plasma cell --> Secrete high affinity ab, live for years

Spleen--> Bm --> High frequency, develop into plasma cells 

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Immunological challenges

Type 1 Hypersensitivity/Allergy

Atopy- inherited predisposition 

Pollen--> APC MHC 2--> CD4+ T cell--> IL-4--> Th2--> IL4,5,13--> B lymphocyte--> P--> IgE--> Mast cell

Asthma, perennial rhinitis, ecxema, anaphylaxis

Autoimmunity

Grave's Thyroiditis- Th2--> B cell --> P--> TRAb autoantibodies --> TSH-R/ -->EXCESS THYROID HORMONES

Diabetes Type 1- Islet cell autoantibodies: Insulin, GAD65, IA-2, ZnT8

APC/HLA--> T --> CD8 Tc --> Kill B cell 
Th1/17 (IFNy,TNFa/IL-17)--> B lymphocyte--> P --> Autoantibodies + Macrophage  

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Immunodeficiency

Absent thymus- severely reduced T cell number and function- DiGeorge

Defective T cell activation- Reduced T cell- CD3y chain mutation

Defective B cell maturation - Hyper IgM syndrome

Defective APC/T cell interaction- Reduced granuloma and IFNy receptor deficiency

Neutrophil failure- chronic granulomatous diasease 

SCID 

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Microbiology

Animal and plant cells: Cell membrane, DNA & RNA, 80S (or 70S) Ribosomes 10-100um

Bacteria: Cell wall and membrane, DNA & RNA, 70S Ribosomes 0.3-3um

Viruses: DNA or RNA, Nucleocaspid 20-200nm 

Gram positive: blue/purple low lipid exotoxins 

Gram negative: red high lipid endotoxin, don't survive drying


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Gram Positive Bacteria

Gram Positive Cocci: 

Staphylococci (Clusters)

Staph. aureus: PVL, aby toxins, Enterotoxins A-F (E= TSST1), coagulase positive, protein A 

Boil

Streptococci (Pairs/Chains)

a Haemolytic: Strep. pneumoniae 

b Haemolytic: A (pyogenes) Streptolysins, kinase, hyaluronidase B C 

Cellulitis, pharyngitis and rheumatic fever (pyogenes)

Non-haemolytic: enterococci, anaerobes 

Gram Positive Rods: 

Anthrax, Tetanus, Botulinum (Spores)

Diphteria, Nocardia (No Spores)

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Gram Negative Bacteria

Gram negative cocci

Gonorrhoea, meninogoccocal meningitis 

Gram negative rods

E. Coli UTI/peritoneum, Klebsiella, Proteus, Pseudomonas (aeruginosa) Contact lenses, infection leukaemics, ITU- enzymes, elastase, endotoxin 

Shigella, Salmonella, Campylobacter, Brucella, Legionella, Anaerobes, Haemophilus 

Fungi

Mould: Aspergilus, Mucor

Yeast:Candida

Dimorphic Fungi: Histoplasma

Parasite

Protoza: malaria, amoeba 

Helminth- Nematode- roundworm
Trematode- flukes  

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Fever and Sepsis

Fever 

1. TNFa/IL-1/IL-6 increase in blood from macraphages, monocytes and B cells

2. Hypothalmic thermoregulatory centre PGE2 - IgG 

3. Elevation of set point 

Sepsis

Exotoxin: TSST1 SPEA/C
Endotoxins: LPS  

AIDs

Infection with unusual pathogen: Pneumocystitis, mycobacteria

Reactivation or severe infection: Toxoplasma, PCP, CMV 

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Viral Infections

DNA Virus: Icosahedral, Spherical

Parvovirus: parvovirus B19 **
Papovirus: papillomaviruses ds
Hepadnaviridae: hepatitis B ds envelope 
Adenoviridae: resp tract, eye ds
Herpesviridae: herpes simplex, VZV, CMV, EBV ds 

RNA Virus: 

Picornaviridae:spherical, icosahedral **+ -rhinovirus, polio
Orthomyxoviridae: spherical/filamentous and helical **- envelope - influenza A/B
Paramyxoviridae:spherical/filamentous and helical  **- envelope - mump, measle
Retroviridae: spherical **+ envelope- HIV1/2

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Viral Infections

HIV 1: CD4/ CXCR4 T cells/ CCR5 macrophages 

Rabies: ACh

EBV: C3d receptor B cells

Vaccinia: EGFR

Reovirus Type 3: B adrenergic hormone receptor

Rhinovirus: Glycophorin A molecule

Influenza: Sialic acid on glycoproteins (glycophorin A molecule)

Encephalomyocarditis: Glycophorin A molecule  

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Inflammation

Exudate: Inflammatory extravascular fluid with high protein conc. and much cellular debri S.G>1020

Transudate: Ultrafiltrate of low protein (albumin) S.G. < 1012

Pus: Exudate in Neutrophils and parenchymal cell debri

Chemotaxis Neutrophils-->

  • Bacterial products
  • c5a
  • LB4 (arachiodonic metabolism in lipoxygenase pathway)

Acute suppurative inflammation (pus) appendicitis

Acute fibrinous inflammation pneumonia

Acute membranous inflammation psudomembranous colitis 


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Chronic Inflammation

1. Infiltration by macrophages, lymphocytes and plasma cells

2. Proliferation of fibroblasts and small blood vessels 

3. Granuloma (lymphocytes and macrophages) 

Pulmonary TB 

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