Phase 1

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

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 

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

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)

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 

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

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 

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 

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  

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 

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

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)

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  

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 

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

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  

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 

1. Infiltration by macrophages, lymphocytes and plasma cells

2. Proliferation of fibroblasts and small blood vessels 

3. Granuloma (lymphocytes and macrophages) 

Pulmonary TB