1. Julian DG, Cowan J M, Mchenachan J M. cardiology. Edinburg:Elsevier; 2005

2. Fuster V, Alexander R W, O’Roucke A. Hurt’s The Heart. 11^th edn. Newark:McGraw Hill;2004

3. Black JM, Hawks JH. Medical – Surgical Nursing: clinical management for positive outcomes. 7^th ed. Saunders: Elservier;2004.

4. Lewis SM, Heitkempter MM, and Dirksen SR.Medical-Surgical Nursing: Assessment and management of clinical problems. 6^th edn. Philadelphia:Mosby;2005

5. Luckmann, Sorensen’s . Medical – Surgical nursing : A psycho physiologic approach . 4^th ed. WB Saunders company : Philadelphia.

6. http://medlineplus.gov/http://medlineplus.gov/

7. http://www.nlm.nih.gov/medlineplus/ency/article/000194.htm

8. http://www.mediawiki.org/http://www.mediawiki.org/

9. http://wikimediafoundation.org/http://wikimediafoundation.org/

10. http://en.wikipedia.org/wiki/Cardiac_tamponade

11. Sharma S K, Mohan A. extrapulmonary Tuberculosis. . Indian Journal of Medical Research. New Delhi: 120(4)316-38 :2004

Kothari SS, Juneja R. Tuberculosis and the heart. Tuberculosis. New Delhi: Jaypee Brothers Medical Publishers; 229-36:2001

It is a functional joint disorder, characterized by progressive deterioration and breakdown of articular cartilage, mainly in weight-bearing joints and is essentially non-inflammatory in nature.

Note: Charcot joint is an extreme form of osteoarthritis seen in patients with neurological dysfunction in which there is rapidly destructive osteoarthritis, the production of loose bodies, severe subluxation and even dislocation of the joint.

Morphology: changes manifest morphologically as alterations in cartilage, synovium and bone…

1. Earliest changes are loss of proteoglycans and decreased metachromasia of the articular cartilage, associated with focal loss of chondrocytes alternating with areas of chondrocyte proliferation (cloning) and increased matrix basophilia.

2. Next, fissuring, pitting, and flaking of the cartilage develop, followed by vertical clefts down to the subchondral bone.

3. Flaking of the cartilage exposes underlying bone, which appears ivory-like (eburnation) as continued joint motion polishes the surface.

4. Subchondral microcysts and fractures may develop.

5. Synovium shows a mild chronic inflammatory infiltrate (non-specific synovitis) can develop osteocartilaginous metaplasia, fragments of which create osteocartilaginous loose bodies (joint mice) within the joint space.

Overview: changes in general forms of arthritis

Cartilage:

• Clefting/splitting

• Cloning repair and metaplasia

• Loss of matrix basophilia

• Cartilage necrosis (uncommon)

Synovium:

• Varying degrees of hyperplasia and hypertrophy

• Hemosiderin deposition

• Reaction to joint wear / breakdown products

• Presence of loose bodies

Bone:

• Superficial areas of subchondral necrosis

• Reactive sclerosis and cystic change

• Microfractures

• Formation of osteophytes

Synovial fluid:

• Infiltrates (inflammatory or otherwise)

• Pathogens

• Various substances and crystals

-performed either immediately before induction of anaesthesia or immediately after induction.

The suitability of the patient for this procedure must be established in advance.

The haemoglobin and haematocrit should be "normal"; eg Hb preferably above 12 g/100 ml.

The cardiovascular system must be such as to be able to compensate for the reduced oxygen carrying capacity.

Technique.

2 IV cannulae in different sites eg arms - one large (eg 12G) to collect blood, the other usual size for fluids and drugs.

Bleed a pre-determined volume of blood (to h'crit not less than 27) into packs with anticoagulant, in the prescribed manner, label and number in order of taking.

Meanwhile replace volume with N/Saline or N/Saline and colloid.

Leave the collected blood on the anaesthesia trolley.

When blood loss is finished , or is minimal (ie at or near end of surgery) re-infuse blood, beginning with the last unit taken, so that the last blood to be re-infused is that taken first and therefore that with the highest haematocrit (given when no further significant blood loss expected).

Bacterial meningitis is a devastating disease, if left untreated it results in death. Essentially it is an inflammation of the meninges. There are different types of bacteria that cause meningitis in neonates, elderly, and infants and children. Meningitis is rare between the ages of 20-60.

1. Neonates – Group B Strep, E. coli K1

2. Infants and children – H. influenza, Neisseria Meningitis, S. pneumoniae

3. Children and adolescents – N. meningitis

4. Elderly – S. pneumonaie

H. influenza also causes ottitis, and S. pneumonaie also causes pneumonia, but the rest of the bacteria listed above only cause meningitis.

Infection starts with the respiratory tract  adhesion  bloodstream  meninges. There is often no clinical manifestation before onset of the meningitis.

N. MENINGITIS

This is the most important one because it can infect infants thorugh adults. It’s a Gram – cocci and is closely related to N. gonorrhea. It has a huge antiphagocytic capsule. IgA may actually protect the bacteria because it can block IgE or IgM binding and it can’t activate compliment.

1. Droplet Infection 

2. URTI 

3. Pilli adhesion 

4. Colonize nasopharynx (can stay here for a long time because it’s favorite host is human) 

5. Growth 

6. Get into deep tissue 

7. If have predisposing factors like viral infection, excess IgA, or compliment deficiency, disease develops 

8. If multiplies in blood can have menigococcemia – the release of LPS leading to toxic shock syndrome.

The best way to protect people would be to have an antibody against the capsule. There are 13 different serotypes with distinct polysaccharides, but there is one problematic capsule, it’s made of sialic acid, which is a self-antigen.

HAEMOPHILUS

Unique to infants. H. influenza is the leading cause of ottitis media and meningitis. It is a Gram – rod and has a crescent shape. There are several species. H. ducrei causes an STD. The bacterium needs the growth factors hematin and NAD. There are 6 types of factors A-F. B is the most prevalent, so we vaccinate against it. Same mechanism of infection as N. meningitis.

The mother gives antibodies to the newborn, but they decrease and eventually the baby builds up her own resistance because of colonization. However there is a period between the ages of 1 and 5 where there is little antibody. That is when this bacteria comes acallin.

There is a vaccine vs. the capsule. It is usually conjugated with the diphtheria toxoid. All babies get this vaccine.

GROUP B STREP

S. agalactia looks a lot like GAS. It has an antiphagocytic capsule with sialic acid (a self-protein). There are 6 serotypes. Lipoteichoic acid is used for adhesion. The difference is that it has no toxins.

E. coli K1 also has polysialic acid. Hey wait a minute!!!! H. influenza, N. menigitidis group B, and Group B Strep all have some form of sialic acid! Maybe there are receptors in the meninges for this acid and that’s why these bacteria cause meningitis.

How does Group B Strep cause meningitis and why in newborns?

1. Group B normally colonizes the vagina, but doesn’t cause disease because it is normal flora 

2. Newborn goes through birth canal 

3. Bacteria can go straight to the meninges if the mother is very heavily colonized (early onset meningitis, usually type I or II capsule). Predisposing factors are premature ruptured membrane, prolonged labor, and pre-term delivery. But we can prevent the problem by giving antibiotics. We could also give a vaccine, but that’s not on the market yet. This bacterium a problem in poor southern areas like Alabama, but these mothers don’t tend to go for swabs to see if they are carrying the bacteria. 

4. Late onset meningitis is within the first month of life from p2p contact like breast-feeding. Usually this bacterium has type III capsule. 

5. Rapid diagnosis is essential, and can be done with latex particles coated with anti-group B polysaccharide.

Ok, so we know that the bacteria go pharynx q GALT w lymph nodes e blood rspleen or liver . Meninges, but how do they do that?

They must leak out of the capillary to the arachnoid space.

1. Gram – cocci do this by passing through endothelial cells.

2. H. influenza is so skinny it can between cells.

3. S, pneumoniae and Group B Strep get phagocitized by monocytes and through chemotaxis are brought to the arachnoid space.

Antiobiotics are the most effective way to prevent permanent damage to neurons!!!

The disease occurs everywhere in the tropics but is especially frequent India, Southeast Asia, Central America and the Caribbean. In 1927-28 there was a large epidemic in Greece in which approximately 2000 people died. Until recently, the infection had been very rare in Africa, except for the east coast (sporadic cases) and parts of the Sahel but the epidemiology of dengue is changing and we can expect the disease to increase in other parts of Africa. The disease is not stable in other parts of the world either. After an absence of 20 years, dengue virus type 3 broke out in the Caribbean in 1994. Dengue can occur as an epidemic, as was recently seen in parts of Central and South America and in 1997 in the islands of the Pacific Ocean. The disease occurs more frequently in the rainy season. In 1998 there was a massive increase in the number of cases in Southeast Asia and South America. In Brazil alone a total of 234,828 cases were reported in the first 4 months of 1998 (almost as many as for the whole of 1997).

Dengue, reservoir

Man is probably the main reservoir of the disease. The significance of a sylvatic reservoir in wild monkeys has not yet been established. There is transovarial transmission of dengue virus in the mosquito and this can be repeated for a few generations without the adults feeding on an infected host.

Dengue, transmission

Dengue virus has 4 serotypes and belongs to the Flaviviridae. Each serotype contains a number of subtypes. The viruses are transmitted by infected female Aedes mosquitoes, of which Aedes aegypti is the most important. The virus multiplies in the mosquito and is introduced into the skin via the insect’s saliva. The mosquito develops a life-long non-cytocidal infection. The virus has an RNA genome. This codes for three structural and seven non-structural proteins. Initially a large precursor protein is made which is then cleaved by host-cell and viral proteases.

Dengue, vectors

Aedes aegypti is the most important vector in Africa, America and Asia. This mosquito prefers a peridomestic setting (near houses). In Africa there is a lightly-coloured peridomestic form and a dark-coloured sylvatic form. A. aegypti has two longitudinal dorsal white stripes and an arched stripe (“lyre”), making the insect easily recognisable. These are insects which prefer to bite during the day (unlike Anopheles). Aedes aegypti not only transmits arboviruses but the mosquitoes also have an annoying biting habit ("nuisance mosquito”). They bite during the day, mainly in the late afternoon. They buzz a little but do not keep people awake with the noise they make (unlike Culex mosquitoes). Traditionally it was thought that Aedes aegypti had limited flying ability (100 m). This was called into question by more recent data. Studies with labelled mosquitoes revealed an area of ± 840 meters in diameter in which eggs were laid. The insects are labelled by allowing them to feed on blood to which rubidium chloride (RbCl) had been added as a marker. Rubidium is an alkaline metal which is very similar to potassium and is not toxic in low concentrations. The element is then present in the eggs and can be detected by atom-absorption spectroscopy. It is also possible to trap adult mosquitoes, label them (e.g. with fluorescent dyes), release them and then recapture them later (“mark-release-recapture”). Adult mosquitoes can be trapped for epidemiological reasons, on a person for example (“human bait”) or through various techniques such as insect traps with bait such as CO₂, octenol, light, heat and/or mechanical suction. It is however possible that the sample of insects which is caught in a certain way, differs in composition from the population which is responsible for transmission under natural conditions. In order to study the density of vectors in an area, entomological surveys are used. A frequently used index is the number of positive water containers per 100 houses (“Breteau index”). The “house index” is also frequently used (percentage of houses which are positive for Aedes larvae). If the density is low (e.g. Breteau lower than 5) “ovitraps” can be used to collect the eggs (usually black glass beakers with some clean water and a piece of cardboard, hay or twig in it). These can also be used for surveillance e.g. around seaports and airports.

• Clinical: biphasic flu-like syndrome with severe muscle pain and sometimes rash. Sometimes positive tourniquet (= Rumpel-Leede test) with DHF: petechiae appear after applying a sphygmomanometer to the upper arm. The sphygmomanometer is inflated to halfway between the systolic and diastolic blood pressure. The meter is left in place for 5 minutes. Afterwards one looks for petechiae in the crease of the elbow. If there are more than 20 in a 3 cm diameter circle, the test is positive. This indicates significant capillary fragility, thrombocytopenia or disturbed blood platelet function.

• Laboratory: thrombocytopenia and leukopenia; raised haematocrit due to haemoconcentration. This haemoconcentration is the result of a “capillary-leak” syndrome, with effusions in the pleura and/or ascites accompanied by hypoalbuminaemia (fluid loss from the blood circulation).

• Serology: retrospectively, serological determination of antibodies is possible. There is considerable cross-reaction between the different dengue viruses. An important new development is the dengue ICT test. With this, both the IgM and IgG antibodies can be detected very quickly (in a few minutes). The test is however quite expensive. Its reliability needs to be tested further, but ELISA is probably better. Flaviviruses share antigenic epitopes, which elicit cross-reacting antibodies. These cross-reactive responses can confound the interpretation of serological tests, and it is often impossible to determine with certainty the infecting virus without resorting to performing neutralization tests.

• Antigen detection. A dengue antigen detection assay is also available. This will be positive during the early viraemic phase.

The course of the infection may be asymptomatic, atypical, “classical” or can evolve to a haemorrhagic syndrome with or without shock.

*

Classical dengue fever begins fairly suddenly with fever, headache and sometimes lymphadenopathy. There is no splenomegaly. There is marked muscle pain (breakbone fever), especially in the back and in the extraocular eye muscles (pain behind the eyes when looking sideways). The course of the fever is typically in two episodes (biphasic fever). A rash may appear around the 3^rd to 5^th day in a minority of patients. After the fever has disappeared, recovery may be long and difficult.

*

Complicated dengue is rare. Sometimes dengue infection is accompanied by haemorrhaging (Dengue Haemorrhagic Fever) and/or very low blood pressure (Dengue Shock Syndrome). This may be dramatic and mortality is high (50% without treatment). This occurs mainly in children. The cause of this serious course is not an infection with a more virulent virus. Dengue infection leads to the development of circulating antibodies. These mainly protect against the serotype involved (“neutralising” antibodies). However, sometimes these antibodies enhance virus multiplication and cause an increase in the severity of disease following symptoms infection with a different serotype. After infection there is probably life-long immunity against the serotype which caused the infection. In DHF, one can expect :

• fever

• haemorrhagic complications or positive tourniquet test

• thrombocytopenia <>

• signs of plasma loss such as pleural fluid, ascites, hypoproteinaemia, an increase in the haematocrit to > 20% above normal or a drop in the haematocrit of > 20% after hydration.

*

The severity of the condition (DHF/DSS) can be given by a clinical score:

• Grade 1: thrombocytopenia (<100,000/µl>20% of the starting value)

• Grade 2: idem as 1 + spontaneous haemorrhages or positive tourniquet test

• Grade 3: idem as 1 or 2 + hypotension

• Grade 4: idem as 3 but the blood pressure is not measurable

The prototypical viral haemorrhagic fever is Yellow Fever. Other less well-known fevers are Omsk Haemorrhagic fever (Siberia, transmission via hard ticks and via contact with muskrats), Kyasanur Haemorrhagic fever (Karnataka, India) and Crimean-Congo Haemorrhagic Fever (transmitted by ticks, infected blood and nosocomially). Not all viral haemorrhagic fevers are however arboviruses. Various Arenaviruses (Lassa, Junin and Machupo) and Hantaviruses can lead to haemorrhagic fever, but are transmitted by rodents (“rodent-borne”) and other small mammals. Filoviruses cause severe bleeding, and are thought to be transmitted via infected monkeys / apes and via nosocomial transmission. Even haemorrhagic smallpox existed, but there the transmission was aerogenic. Haemorrhagic measles occurs occasionally, but this is usually not classified as a viral haemorrhagic fever.

Low blood platelets occur in a large number of febrile illnesses, including:

• Septicaemia, including Gram-negative bacteria, typhoid, leptospirosis and borreliosis

• Rickettsioses

• Arboviruses such as dengue or yellow fever;

• Rodent-borne viruses such as Hanta and Lassa fever

• HIV

• Malaria

• Visceral leishmaniasis

• TTP-HUS (thrombotic thrombocytopenic purpura – haemolytic uraemic syndrome): often after colitis which was treated with antibiotics (lysis of Shiga-toxin containing bacteria).

Human antibodies exhibit an enormous range (~108) of specificity’s. The genetic basis for this involves several factors:
A. VDJ recombination

1. the heavy chain of the immunoglobulin is made up of a variable (V), diversity (D), and junctional/joining (J) segment.

2. The gene possesses greater than 200 V, 20 D, and 6 J coding sequences.

3. During B cell development the sequences between the V, D, and J sequences are removed via recombination to provide for a single open reading frame.

4. Heavy chain recombination precedes light chain rearrangement.

5. The light chains can utilize either the kappa or lambda genes for generation of a functional Ig protein.

6. Light chain possesses V and J segments: No D

7. During B cell development, the sequence between the V segment (more than 100 coding sequences) and the J segment (1 or more J segments, depending on the light chain) is removed via recombination to provide for a single open reading frame.

B. Class switching

1. Only the heavy chain

2. The isotype is defined by those sequences (known as the constant region, i.e. codes for IgG, IgM etc.) that are invariable and downstream of the VDJ recombination.

3. Isotype switching utilizes recombination to remove such constant region sequences so as to allow the VDJ sequence to be placed upstream of different C regions.

C. Affinity maturation

1. After the B cells have been activated and class switched, a portion are found that migrate to the spleen and lymph nodes. Two things happen:

a) rapid proliferation, every 6-12 hours=1 division

b) B cells sustain somatic mutation at Ig chains.

2. Aim of this process is to create Ig with higher affinity for antigen

3. Those B cells that lose affinity for antigen are eliminated.

Class I antigens are found on all nucleated cells (3 gene loci: HLA-A, HLA-B, and HLA-C). Class II antigens are found on immunologic effector cells (e.g. macrophages, B cells, activated epithelial cells; 3 gene loci: HLA-DP, HLA-DQ, and HLA-DR)

1. Familial inheritance

a) Many alleles of class I and class II molecules are present at each locus on chromosome 6.

b) Haplotypes from both parents are inherited and expressed codominantly.

2. Disease associations

a) DR4 Rheumatoid arthritis

b) DR3, DR4 IDDM

c) DR3 Sjogren’s syndrome

d) B27 ankylosing spondylitis

3. Transplant compatibility

a) Matching the donor and recipient at the HLA locus improves graft acceptance

b) Both the donor and recipient are typed for HLA profiles using DNA sequence analysis of the HLA genes or more than 200 specific anti-HLA antisera

c) HLA antigens on allographs stimulate recipient CD4+ T cells which respond by secreting cytokines and by inducing adhesion molecules

(1) IL-2 activates CD8+ T cells to a state of cytotoxicity, thus releasing effector molecules such as perforins

(2) IFN-g activates monocytes/macrophages to expresses delayed type hypersensitivity, resulting in increased lysosomal activity, phagocytosis, respiratory burst and release of TNF-a

(3) Activated selectins, integrins, intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) promote leukocyte extravasion into the graft bed.

d) Acute rejection

(1) Within weeks

e) Chronic rejection

(1) Episodic bouts of rejection, occurring months to years after transplantation

f) Hyperacute rejection

(1) Within minutes—graft never takes because of pre-existing sensitivity

Important cytokines in regulation of the immune response
Cytokine	Source	Actions
Interferon-gamma (IFNγ)	T cells and NK cells	Antiviral activity. Stimulates activation of NK cells, CD8+ T cells and macrophages
Tumour necrosis factor alpha (TNFα)	Macrophages and monocytes	Pro-inflammatory Increases apoptosis and expression of cytokines and adhesion molecules. Directly cytotoxic.
Interleukin-1 (IL-1)	Macrophages and neutrophils	Acute phase reactant Stimulates neutrophil recruitment, fever, T cell and macrophage activation, immunoglobulin production
Interleukin-2 (IL-2)	CD4+ T cells	Stimulates proliferation and differentiation of antigen- T lymphocytes
Interleukin-4 (IL-4)	CD4+ T cells and mast cells	Stimulates maturation of B and T cells, and production of IgE antibody
Interleukin-6 (IL-6)	Monocytes and macrophages	Acute phase reactant Stimulates maturation of B cells into plasma cells
Interleukin-12 (IL-12)	Monocytes and macrophages	Stimulates IFNγ and TNFα release by T cells, activates NK cells

Major properties of the innate and acquired immune response
	Innate	Adaptive
Characteristics	Recognises generic microbial structures	Antigen specific responses
	Immediately mobilised (minutes)	Slow response (days)
	No memory	Memory
	Genetically encoded	Not genetically encoded
	Essentially identical responses in all individuals	Acquired as an adaptive response to exposure to antigen
		Cells must be “educated” within the host because disconnected from evolutionary selection
	Present in invertebrates and vertebrates	Present in vertebrates only
Immune components	External barriers (eg skin)	T and B lymphocytes
	Phagocytes
	Natural killer cells
	Soluble mediators eg complement	Secreted molecules eg antibody
	Pattern recognition molecules	Antigen-specific receptors

Present in babies, and protective

Rapid in onset, but little precision.
No memory, “ knee jerk response”

Can however recognise articles as being foreign

The ER “medical technician”

Macrophages –

Very important, particularly in this early immune response

Phagocytosis – recognise and remove unwanted particles

Secrete lysozymes to break down and kill particles

Secrete interferon to activate anti viral mechanisms

Secrete molecules to activate , eg cytokines

Complement

The complement system is a group of more than 20 tightly regulated, linked proteins that act to promote inflammation and eliminate invading pathogens. Complement proteins are produced by the liver, and are present in the circulation as inactive molecules. When triggered, they enzymatically activate other proteins in a rapidly amplified biological cascade analogous to the coagulation cascade.

There are three mechanisms by which the complement cascade may be triggered.

• The alternative pathway is directly triggered by binding of C3 to bacterial cell wall components such as lipopolysaccharide of gram negative bacteria and teichoic acid of gram positive bacteria.
  
• The classical pathway is initiated when IgM or IgG antibody binds to antigen, forming immune complexes. This induces a conformational change in the antibody, exposing a binding site for the first protein in the classical pathway, C1. Changes in C1 after binding result in activation of the cascade.
  
• The lectin pathway is activated by the direct binding of mannose binding lectin to microbial cell surface carbohydrates. This mimics the binding of C1 to immune complexes, and directly stimulates the classical pathway, bypassing the need for immune complex formation.

Activation of complement by any of these pathways will result in the activation of C3, the major amplification step in the complement cascade. C3 activation is followed by the final common pathway, where the complement proteins C5-C9 assemble together to form the membrane attack complex. This can insert into and puncture target cell walls, leading to osmotic cell lysis. This step is particularly important in the defence against encapsulated bacteria such as Neiserria and Haemophilus influenza.

The complement fragments generated by activation of the cascades can also act as opsonins, rendering microorganisms more susceptible to phagocytosis by macrophages and neutrophils . In addition, they are chemotactic agents, promoting leukocyte trafficking to sites of inflammation. Some fragments act as anaphylotoxins, binding to complement receptors on mast cells and triggering release of histamine, which increases vascular permeability.

The products of complement activation also help to target immune complexes to antigen presenting cells, providing a further link between the innate and the acquired immune systems. Finally, activated complement products dissolve the immune complexes that triggered the cascade, minimising bystander damage to surrounding tissues.

The specialists.

Able to individualise treatment to the actual situation, and are better prepared and much faster the next time. The adaptive system amplifies the immune response and enhances the innate system eg phagocytosis and complement

HLA/MHC

Name tag system – indicates to the lymphocytes “please have a look at this particle, and see if its ok…..”

Like presenting wares at a market for the diverse T cells to look through

Class I presents particles for any cell with an internal problem to allow T-helper and T-cytotoxic cells to consider eg viral infection, cancer . The T helper cell activates the B cells to produce antibody, and activates the cytotoxic T cells to kill the cells.

Class II presents external particles, such as debris or invaders which has been picked up by surveillance “antigen presenting cells”, such as DCs or macrophages. They present to the T cells which respond by producing cytokines which activate inflammation and B cells.

T Lymphocytes

There are two types of T cells:

CD8+ cytotoxic T cells which act by recognising HLA Class I presentation of antigen and kill the cell

CD4+ helper T cells, which orchestrate the whole adaptive immune system. After antigen presentation, they release cytokines, which influence other cells. The cytokines they produce determines the type of reaction that results (ie which cells are activated and recruited, and which antibodies the B cells produce). The types of cytokines release can be divided into two groups, Th1 and Th2….the two main subgroups of CD4+ T helper cells.

B Cells and Antibodies

B cells recognise antigens via the antibodies on their surface which act as receptors

They internalise these antigens, and then present them via HLA Class II to the lymphocytes (once again, “please have a look at this particle, and see if its ok…..”). If the T cells responds with activation, it will release cytokines, which enable the B cell to mature and produce more specific antibodies via somatic hypermutation

The roles of antibodies are diverse:

1. Activate complementADCC – Antibody Dependent Cellular Cytotoxicity (NK cells and macrophages)
2. Neutralisation of toxins (eg the gut)
3. Opsonisation to enhance phagocytosis
4. Mucosa Protection
5. Agglutination – form immune complexed which can then be cleared by red blood cells

A. Results when the body fails to recognize the difference between "self" and "non-self" antigens or epitopes, and mounts an immunologic response to those antigens.

B. May be T cell or B cell mediated.

C. Of two types:

1. systemic, involving multiple foci
2. Organ specific

A. Release of sequestered antigen-

A sequestered antigen is one that under normal conditions is not readily available for recognition by the immune system, even though it is present in the body. Release of sequestered antigens is often caused by tissue injury. When the antigens are released, normal immunologic response occurs, i.e. antibody production, but since these antibodies are directed against self-antigens, they are called autoantibodies.

Examples:

• anti-sperm antibody following vasectomy
• anti-lens antibody following eye injury
• Sympathetic Ophthalmia
• anti-cardiac muscle antibody following MI
• anti-corneal antibody following contact lens trauma

B. Altered Antigen (Neoantigen)

It is known that autocoupling haptens can cause formation of neoantigens that are recognized as foreign by the body (i.e. poison ivy, etc.). While the altered antigen theory is technically possible in the development of autoimmune disease, no convincing evidence of this etiology has been presented to date.

C. Shared or Cross-Reactive Antigen Theory

The cause of this autoimmune mechanism is exogenous antigens that share with the body several, if not many cross-reacting epitopes. Exposure and response to these exogenous antigens results in the formation of antibody which will then cross react with self antigens.

Examples:

• Autoantibody induction in paroxysmal cold hemoglobinuria secondary to T. pallidum infection (syphilis)
• Hemolytic anemia associated with mycoplasma infections
• Post-vaccinial and post-infectious encephalomyelitis
• Group streptococcus induced rheumatic fever

Autoantibodies not associated with true autoimmune disease:

Syphilis-

T. Pallidum infection -----> tissue destruction Tissue destruction -----> exposure of Ag determinants (Specifically cardiolipin) Abs formed against cardiolipin.

D. Polyclonal Stimulation of T cells and/or B Cells

A variety of bacterial products, some viruses and viral components (such as EBV), parasites, and some drugs may act as B cell mitogens. Normally in the body, according to theory, there are a certain number of clones of B cells that are not tolerant to self. These cells are not normally stimulated because there is no enhancement by Th (helper) cells. In the presence of a B cell mitogen, however, B cell clonal proliferation would occur in the absence of T cell enhancement, resulting in the formation of antibody by these non-tolerant cells, i.e. autoantibody. This type of mechanism has been demonstrated in vitro, and the antibodies produced appear to be:

1. Transient
2. Of low affinity
3. IgM primarily

E. Alteration of Normal Homeostatic Mechanisms

"Forbidden clone" theory

In the normal individual, Ts (suppressor) cells tend to prevent activation of non-tolerant clones of lymphocytes. Loss of a given antigen-specific Ts cell subset could result in the activation of non-tolerant clones and formation of autoimmune disease. There is evidence of Ts deficiency in many of the autoimmune disorders, and this theory lends considerable support for the increased incidence of autoimmune disease in the elderly. There have been a number of studies that document Ts deficiency in aged patients with autoimmune disease.

F. Genetic Factors

There have been a number of studies that show an association between certain MHC haplotypes and autoimmune diseases. SLE: A1,B8,DR3; RA:Dw4,DRw4). It has not yet been possible to attribute autoimmune disease predisposition to a single genetic locus, however. However evidence is clear that genetic factors play a definite role in the mechanisms of these diseases.

G. Hormonal Factors

Sex hormones, and or X or Y linked genes may play a role in the formation of autoimmune disease. In general, females are more susceptible to connective tissue diseases than are males. The incidence of SLE in females after puberty is 9 times that of men. The incidence of ankylosing spondylitis is higher in males than in females. Experimental and clinical studies in humans and animals tend to incriminate the sex hormones, rather than some X or Y linked genetic locus.

Systemic Lupus Erythematosus-Systemic

In this disease, autoantibodies are formed which include anti-DNA, anti-RNA, and anti-cardiolipin. The antibodies form complexes (immune complexes) with the antigens to which they are directed. These immune complexes can form anywhere in the body, including the kidneys, where deposition within the glomerulus can result in glomerulonephritis, and kidney failure. Also, formation of anti-cardiolipin antibody may result in a FALSE POSITIVE RPR, when doing reagin-screening tests for syphilis.

Clinical Features:

1. anemia
   
2. leukopenia--anti-Abs usually present
   
3. thrombocytopenia
4. Prolonged clotting time
5. May have anti-clotting factor Antibodies
6. Vasculitis
7. Glomerulonephritis
8. Joint Damage Due to Ag/Ab complex deposits in synovial fluid
9. Most tissue damage is due to these immune complex deposits

Hashimoto's Thyroiditis-Organ Specific

Hypothyroidism characterized by:

• infiltration of lymphocytes into thyroid gland
  
• thyroid hormone insufficiency
• anti-thyroglobulin antibody
• T cell mediated
• organ specific autoimmune disease

Grave's Disease-Organ Specific

B cell mediated hyperthyroidism caused by an IgG antibody that mimics the activity of TSH. This autoantibody is call LATS (long acting thyroid stimulator).

Guillain-Barré Syndrome-Organ Specific

Seen in come cases where living viral organisms are utilized for vaccination purposes. Very low incidence, but is an example of a post-vaccinial or post-infectious encephalomyelitis. Viral pathogens attack various tissue cells, including cells of the CNS. Affected cells of the CNS may be attacked by activated T cells, resulting in demyelinization of nervous tissue. Symptoms include backache, headache, muscle weakness (even paralysis), and loss of reflex responses. The disease is USUALLY self-limited, however some deaths have been reported. It may be that the self-limitation of the disease is due to the autoantibodies formed acting as blocking antibodies to the viral antigens, and preventing further recognition and response.
Paroxysmal Cold Hemoglobinuria- AHA Organ Specific

Antibody formed is usually anti-I against I antigens on cell surface of red cells. It is a complement dependent, cold reacting antibody causing hemolysis if cells are cooled, then rewarmed to body temperature. Cooling can occur, for example, when extremities are exposed to cold, or during certain types of surgery where body temperature is lowered.
Rheumatoid Arthritis-Systemic

• Etiology unknown
• RF is an IgM anti-IgG antibody that will react in vivo
• Stimulus for production is unknown
• RF is also seen in several other connective tissue disorders

Pernicious Anemia-Organ Specific

1. Inflammation and subsequent atrophy of gastric mucosa
2. Results in inability to secrete HCL, Intrinsic Factor, and pepsin
3. Macrocytic anemia
4. 95% of patients have demonstrable anti-parietal cell antibodies & or anti-Intrinsic Factor antibody
   

Goodpasteur's Syndrome-Organ Specific

1. Glomerulonephritis with pulmonary hemorrhages
2. Anti-glomerular basement membrane antibody
3. Lung damage---->formation of Ab----> Ab cross reacts with glomerular basement membrane producing glomerulonephritis

Found on:	cluster designation:	binds to:	effects.
	CD 2	LFA-3
T helper	CD 4	MHC II	Exogenous Ag
T killer	CD 8	MHC I	Endogenous Ag
leukocyte	CD11 / CD18	ELAM-1	adherence to endothelium
	CD 28	B7 (CD 80 / CD 86)	co-stimulation. IL-2.
endothelium	CD 34	L-selectin	binds lymphocytes
B	CD 40	CD 40 ligand on T	class switching.
cancer	CD 44	endothelium	needed for metasis
endothelium	CD 54 ICAM	CD 18 LFA1(integrin)	binds lymphocyte
endothelium	CD 106 VCAM	CD29/CD49 VLA	binds monocyte
endothelium	ICAM (Ig like)	LFA-1 (integrin)(CR3) Mo-1	lymphocyte neutrophil
endothelium	VCAM (Ig like)	VLA-1 (integrin)	monocyte
endothelium	E-selectin (lectin)	CD 15 glycolipids	neutrophil, T, monocyte
endothelium	P-selectin (lectin)	glycolipids	neutrophil, monocyte
non-CA cells	MHC	NK cells	phosphatase turns off nk

submandibular gland (or sublingual but not parotid)

• ***Serous Demilune***

• Be able to distinguish between mucous unit (lighter) and serous unit (darker)

kidney

• simple squamous epithelium (parietal layer of Bowman’s capsule)

• simple cuboidal epithelium (around the ducts)

skin (thin, not palmar or plantar)

• stratified squamous keratinized (you must say keratinized or it will be wrong) epithelium

• dense irregular connective tissue (dermis)

• this is collagen type 1 (pink)

• stratified cuboidal epithelium (around the sweat duct)
  

• adipose tissue (looks like chicken wire)

• sebaceous gland

  • cells with foamy appearance associated with a hair follicle and not found in thick palmar or plantar skin-no one has hairy palms-hopefully anyway)

esophagus

• stratified squamous non-keratinized epithelium (also found in the vagina) *remember to write non-keratinized or it will be wrong

• loose aerolar connective tissue (underneath the epithelium)

jejunum

• simple columnar epithelium with goblet cells and brush border (you must write out that entire name or it will be wrong)

• Paneth cells (this is another one that he always asks)

• popular secondary question:what does it secrete?-lysozyme*

• plasma cells (black dots in the loose areolar connective tissue)

  • part of the immune system and necessary because of the nasty stuff we eat especially in Dominica!

ileum (you can also use colon)

• myenterric (Auerbach’s) plexus

  • parasympathetic plexus located between the two layers of smooth muscle and is found through the GI tract

stomach

• simple columnar epithelium (also in gallbladder)

  • notice the lighter color staining because each cell is mucous secreting

  • therefore NO goblet cells or brush border

bladder (or ureter)

• transitional epithelium (dome shaped and/or bi-nucleate cells)

trachea

• ciliated pseudostratified columnar epithelium with goblet cells

  • also refered to as respiratory tract epithelium but do not write that name on the exam

epididymis

• pseudostratified columnar epithelium with stereocilia

• remember that stereocilia are just long microvilli (actin microfilaments) so they are not real cilia

Note: here is a hint about the pseudostratified epithelia, the above two examples are the only instances where you will see them therefore, if it does not have either cilia or stereocilia, IT IS NOT PSEUDOSTRATIFIED even if it looks like it might be! You will also never see cilia or stereocilia on any other epithelium therefore, to determine if it is pseudostratified, first look for either one of those two surface specializations. This is a constant rule so use it for your practical!

tendon

• dense regular connective tissue (do not call this tendon on the exam)

• looks very much like smooth muscle and longitudinal section of nerve *therefore compare the three side by side to see the subtle differences

hyaline cartilage

• chondrocyte cell in a lacuna (you have to write lacuna otherwise it is wrong)

• isogenous group (remember this is interstitial growth)

• territorial and inter-territorial matrix

  • territorial matrix is darker because of the preponderance of GAG’s

  • remember this is collagen type 2 (type 2-blue)

• perichondrium

• remember this part is collagen type 1 (pink)

developing membranous bone (fetal finger)

• perichondrium vs. periosteum

  • just what the name says, if it is the part over the cartilage it is perichondrium if it is over bone it is periosteum. These two structures are continuous with each other.

• know the five zones (resting, proliferating, hypertrophy, calcification, and ossification) remember that the process here is endochondral ossification

• **Sharpey’s fibers simply connects the periosteum to the bone collar

• bone collar (remember this is direct bone formation)

• cell types: osetoclast (large multinucleated), osteocyte and osteoblast

Note: One question that everyone seems to ask me is the difference between appositional, interstitial, direct and endochondrial bone formation. I know it has nothing to do with your slides but since it is confusing I will mention it.

First, you are describing two separate things that is growth vs. bone formation. They do not mean the same thing. When talking about growth you use the terms appositional and intramembranous to describe it.

Appositional (bone and cartilage) is when cells (...blasts) move from the outside in and become (...cytes). Interstitial (cartilage only) is when the chondrocytes divide within the middle of the cartilage and form isogeneous groups that eventually spread out. Bone formation refers more to the embryology of bone. Direct or intramembranous bone formation is what happens in the bone collar. Bone is directly made from embryonic mesoderm. Endochondrial bone formation is just what the name says, cartilage is made first then it turns to bone (indirect) and this is what is happening in the epiphyseal plate.

compact bone

• Haversian system or osteon

• osteocyte in a lacuna (must write lacuna)

• canaliculi (house cytoplasmic extensions of the osteocyte cell)

• interstitial lamella

  • broken down osteon that looks like nothing significant in between osteons