1.  cell size - enlarged in necrosis, reduced in apoptosis.

2.  nucleus - pyknosis -> karryorrhexis in necrosis and fragmentation in apoptosis.

3.  plasma membrane disrupted in necrosis, intact with altered structure in apoptosis.

4.  cellular contents - enzymatic digestion and contents may leak out of cell in necrosis, released in bodies in apoptosis.

5.  adjacent inflammation in necrosis, no adjacent inflammation in apoptosis.

6.  necrosis is pathological.  Apoptosis mostly physiological but can be pathological.

what is innate immunity?

what are the major components?

innate (natural immunity) - defence mechanisms that are present even before the infection and have evolved to specifically recognise microbes and protect against infection.

Major components:  epithelial barriers that block the entry of environmental microbes, phagocytic cells (mainly neutrophils and macrophages), NK cells and several plasma proteins including complement.

Toll like receptors are membrane proteins that recognise a variety of microbe derived molecules and stimulate innate immune responses against microbes.

what is adaptive immunity?

components of adaptive immunity?

adaptive immunity consists of mechanisms that are stimulated by (adapt to) microbes and are capable of also recognizing non microbial substances - antigens.

consists of lymphocytes and their products, including antibodies.  The receptors are much more diverse than those of the innate immune system.

2 main types of adaptive immunity:  

- cell mediated - intracellular microbes mediated by T-lymphocytes.

- humoral - protects against extracellular microbes and their toxins, mediated by B lymphocytes.

lack of differentiation.

malignant neoplasms composed of undifferentiated cells are said to be anaplastic.  Lack of differentiation or anaplasia is considered a hallmark of malignant transformation.

- generated from immature precursors in the thymus.

- found in the blood, lymph nodes, spleen.

- each T cell is genetically programmed to recognise a specific cell bound antigen via an Ag Specific T cell receptor (TCR).  Cannot be activated by soluble antigens.  Therefore the presentation of processed membrane-bound antigens by antigen presenting cells is required for induction of cell-mediated immunity.

- also express a number of functions - associated molecules (CD4, CD8, CD2 integrins) which act as co-receptors in T cell activation.

- b lymphocytes develop from immature precursors in the bone marrow.

make up 10-20% of circulating peripheral lymphocyte population as well as in the lymph nodes, spleen, tonsils and GIT.

- recognise Ag via b-cell Ag receptor complex.

- other receptors on B cells - includ complement receptors, Fc receptors and CD40.

- B cells activated by protein and non protein antigens -> differentiation into AB secreting plasma cells.

- macrophages that have phagocytosed microbes and protein antigens process the Ag and present peptide fragments to T cells.

- important effector cells in certain forms of cell mediated immunity, such as DTH.  Activated by cytokines which enhances the microbicidal properties and their ability to kill tumour cells.

- important in the effector phase of humoral immunity, by phagocytosing microbes opsonised by IgG or C3b.

- 2 types of dendritic cells - dendritic and follicular dendritic cells.  Langerhans cells are immune epithelia based dendritic cells.

- key role in Ag presentation and are located just below the epithelia and in tissue interstitial.

- express high levels of MHC class II molecules and costimulatory signals - therefore able to present and activate T cells.

follicular dendritic cells are present in the lymph nodes and spleen and can trap antigens bounds to antibodies or complement proteins - ongoing role in immune responses by presenting antigens to B cells.

messanger molecules of the immune system.

short acting soluble mediators that act on a wide number of cells in a variety of different ways.

include lymphokines (lymphocyte derived); monokines (monocyte derived) and interleukins (mediate communication between leukocytes).

- those that mediate innate immunity; IL-1, TNF, type 1 interferons and IL-6.

- regulate lymphocyte growth, activation and differentiation of lymphocytes; IL2, IL-4, IL-12, IL-15, and TGF beta.

- activate inflammatory cells (macrophages, eosinophils, neutrophils and endothelial cells)  INF-gamma, IL-5, TNF and lymphotoxin.

- affect leukocyte movement (chemokines) CC, CXC.

- stimulate haematopoiesis (CSF)

proto-oncogenes are physiologic regulators of cell proliferation and differentiation.

oncogenes are characterized by their ability to promote cell growth in the absence of normal mitogenic signals.

-many individual cytokines are produced by several different cell types.

- actions are pleiotrophic - any one cytokine acts on many different cell types and mediates many effects.

- acts in 3 was:

- auto crine - on the same cell that produces them (IL-2 on T cells).

- paracrine - on cells in the near vicinity (IL-7 acting on B-cell progenitors).

- endocrine - on many cells systemically (IL-1 and TNF).

- cytokines mediate effects by binding to specific high-affinity receptors on their target cells.

typical in all tissues is a type III hypersensitivity with an acute necrotising vasculitis involving small arteries and arterioles.

Kidney:

- injry from immune complex deposition in renal structures:

- Glomeruli, tubular and  peritubular capillary basement membrane, larger BV.

- thrombotic pathology from anti-phospholipid antibodies.

- causes varying degrees and types of glomerulonephritis.

skin:  - erythematous malar rash on face.

- similar rash over extremeties and trunk.

- exacerbated by sunlight.

- also get bullae, urticaria, ulcers and maculopapular lesions.

- histologically -> liquefaction necrosis of basal layer of epidermis.

- deposition of immune complexes at dermal junctions.

joints:

- non erosive synovitis with little deformity.

- acute exacerbations -> exudate of fibrin and neutrophils with perimononuclear infiltrate.

cns:  neuropsychiatric manifestations.

pericarditis/cardiovascular:  

- fibrinous exudate.

- may become thickened in time with obliteration of serosal cavity.

- myocarditis less common.

- non bacterial endocarditis = libman-sacks endocarditis.

spleen - moderate splenomegaly with capsular thickening and follicular hyperplasia.

- perivascular fibrosis -> onion skin appearance.

Lungs - pleuritis with pleural effusion.

- interstitial pneumonitis.

- diffuse fibrosing alveolitis.

chronic disease characterised by dry eyes and dry mouth resulting from immunologically mediated destruction of the lacrimal and salivary glands.

primary form - sicca syndrome.

secondary form - associated with Rheumatoid arthritis, SLE, polymyositis, scleroderma, vasculitis.

chronic disease of unknown aetiology characterised by abnormal accumulation of fibrous tissue in the skin and multiple organs.

classified as:  diffuse scleroderma:  widespread cutaneous and early visceral involvement.  Associated with DNA topoisomerase I ANA.

localised scleroderma (CREST):  minimal cutaneous involvement and late visceral involvement:  Calcinosis, Raynaud phenomenon, Oesophaegeal dysmotility, Sclerodactyly, Telangectasia.

sking:  symmetric oedema and thickening of skin, especially hands, fingers; associated loosely with Raynaud phenomenon.

articular symptoms:  may mimic RA.

dysphagia:  oesophageal fibrosis in 50% of cases.

GI involvement:  malabsorption, abdominal pain, obstructive symptoms.

pulmonary fibrosis:  respiratory or right heart failure.

cardiac:  arrhythmias, heart failure, microinfarction.

malignant hypertension -> renal failure.

- most primary immunodeficiency diseases are genetically determined and affect specific immunity or non specific host mechanisms mediated by complement proteins.

- usually presents around 6months - 2 years of life.

1.  homosexual and bisexual men.

2.  IVDU.

3.  haemophiliacs.

4.  blood component recipients.

5.  heterosexual contact with above groups.

1) direct inoculation into the blood vessels breached by trauma, and 

2) into dendritic cells or CD4+ cells within the mucosa.

The rate of heterosexual transmission has outpaced transmission by any other means.

- CD4+ helper T cell depletion is pathogenic pathways to AIDs.

- CD4 molecule is a high affinity receptor for HIV.

- first step is the binding of gp120 envelope glycoprotein to CD4 -> conformational change that results in the formation of a new recognition site on gp120 for coreceptors ccr5 or cxcr4.

- HIV RNA undergoes transcription in host cell -> integrated in host genome.

- cells affected:  CD4+ lymphocytes, macrophages, monocytes, follicular dendritic cells in lymph nodes.

- Tcell depletion occurs through:  

- intracellular viral replication and cell lysis.

- progressive destruction of lymphoid tissue -> impaired maturation. 

- chronic activation of uninfected cells through HIV and opportunistic infections -> activation-induced cell death.

- fusion of infected and non infected cells through gp120.

- binding of gp120 to non-infected cells -> apoptosis.  CTL death.

- pleomorphism - variation in size and shape of cell and nuclei.

- abnormal nuclear morphology - nuclei disproportionately large for cell, nuclear shape is variable.

- mitoses - large number of mitosis.

- loss of polarity - grow in disorganized fashion.

- giant cells

- changes including loss of the uniformity of individual cells as well as loss in the architectural orientation.

when dysplastic changes are marked and involve the entire thickness of the epithelium but lesion remains confined to normal tissue it is considered "carcinoma in situ".

3 main factors: - the doubling time of tumour cells,

the fraction of tumour cells that are in the replicative pool and 

the rate at which cells are shed and lost in the growing lesion.

1) direct seeding of body cavities or surfaces. usually peritoneal.  however any other cavity - pleural, pericardial, subarachnoid and joint space can be affected.

e.g. ovarian ca.

2) lymphatic spread - spread and growth of ca. or reactive hyperplasia. 

3) hematogenous spread

- composed of abnormal forms of host proteins (PrP)

-cause spongiform encephalopathies (Kuru, Creutzfeldt Jakob disease, bovine spongiform encephalopathy, vCJD)

- disease occur when prion protein undergoes a conformational change that confers resistance to protease.  this in turn promotes conversion of the normal PrP to the abnormal form.

- obligate intracellular parasites requiring the cell's metabolic machinery for replication.

- consist of nucleic acid genome surrounded by a protein coat (caspid) with or without additional lipid envelopes.

- very small (2o-300nm) and can only be seen under electron microscopy.

- cytopathic effects of infected cells may  be seen under light microscopy.

- may be transient (rhinovirus) or cause chronic infections (HCV) or carrier states (VZV, HSV).  May cause transformation into tumour cells (HPV).

what are bacteriophages, plasmids, transposons?

how do they cause human disease?

- mobile genetic elements that infect bacteria and can indirectly cause human disease by encoding bacterial virulence factors (adhesins, toxins, antibiotic resistance enzymes).

- clinical examples include vancomycin resistant enterococci and mehticillin resistant staphyloccoci.

- prokaryocytic - have a cell membrane but no membrane-bound nuclei and other membrane enclosed organelles.

- the cell membrane is made of peptidoglycan.

- 2 forms of cell wall structures:  thick wall surrounding cell membrane (gram positive) and thin wall sandwiched between two phospholipid layers (gram negative).

classified by gram stain (cocci or bacilli) form of respiration (aerobic or anerobic)

can synthesize their own DNA, RNA and proteins but depend on host for favorable growth conditions.

- may have flagella to assist movement; pili to assist attachment to host cells.

- similar to bacteria in that they divide by binary fission and are sensitive to antibiotics.

- lack certain structures (mycoplasma has no cell wall); metabolic capabilities (chalmydia cannot synthesise ATP).

are obligate intracellular organisms.

- eukaryocytic - possess thick chitin containing walls and ergosterol-containing cell membranes.

- grow as either budding yeast cells or as slender filamentous hyphae.

- fungal species that are confined to superficial layers of the dermis are called dermatophyates - e.g. tinea pedis.

- some can invade the subcutaneous tissue causing abscesses or granulomas (tropical mycoses).

- most are commensals in normal host but may cause systemic damage in immunocompromised host (candida, pneumocystis carinii).

- single celled eukaryocytes - can replicate intracellularly within a variety of cells (eg plasmodium in RBCs, leishmania in macrophages) or extracellularly in urogenital system (eg trichomonas vaginalis), GIT (giardia lamblia, entamoeba histolytica ) or blood.

- cause of much disease in developing countries.

- parasitic worms - highly differentiated multicellular organisms with complex lifecycles which can often alternate between sexual in the definitive host and asexual reproduction in an intermediary or vector.

- disease may result from an inflammatory response to eggs or larvae rather than adults and is proportional to the number of organisms that have infected the host.