1. Aplastic anemia

1. dysfunctional or deficient multipotent myeloid stem cells leads to pancytopenia

2. caused by viruses (CMV), radiation, renal failure (decreased erythropoietin)

3. drugs (NSAIDs, benzene, chloramphenicol)

2. Acute blood loss

1. transient normocytic anemia

3. Hemolytic anemia

1. increased RBC destruction
2. leads to increase unconjugated bilirubinemia, hemoglobinemia/uria, decreased haptoglobin
3. increase in retic count secondary to erythropoiesis
4. infections bartonellosis, clostridia, malaria
5. genetic (intracorpuscular) hemolytic anemias

• hereditary ovalocytosis (autosomal dominant)

• hereditary spherocytosis (autosomal dominant) defect in spectrin protein in ECM

• G-6-PD (x-linked) precipitated by oxidative stress, see Heinz bodies

• Pyruvate kinase def (autosomal recessive)

6. acquired (extracorpuscular) hemolytic anemias

• lymphoma, spherocytosis = (+) direct Coomb’s test

• lymphoid neoplasm, ABO incompatibility, Raynaud’s phenomenon = (+) indirect Coomb’s test
  

1. Fe deficiency anemia
   

1. The most common type of anemia and iron deficiency is the most prevalent deficiency state on a worldwide basis.

2. Caused when the dietary intake or absorption of iron is insufficient.
   

3. United States, 20% of all women of childbearing age have iron deficiency anemia. The principal cause of iron deficiency anemia in pre-menopausal women is blood lost during menses. In older patients, iron deficiency anemia is often due to bleeding lesions of the gastrointestinal tract
   

2. Anemia of Chronic Disease

1. usually normocytic, normochromic, and relatively mild, however, when severe, the MCV becomes reduced

2. conditions often associated are inflammatory conditions, malignancy, congestive heart failure, thrombosis, chronic pulmonary disease, diabetes, trauma

3. mechanism of disease is thought that chronic inflammation prevents iron from being released and or RBCs have a shortened life span
   

3. Thalassemias

1. inherited anemias characterized by defects in the synthesis of one or more of the globin chain subunits of the hemoglobin tetramer.
2. quantitative disorder = α or β chains are defective so not enough hemoglobin for RBCS
3. common in patients with Mediterranean backgrounds. 3 type α, β, δ.
   

4. Sideroblastic anemia

1. can be hereditary (x-linked) or acquired (alcohol, isonaizid, chloramphenicol)

2. diagnosed by finding ring sideroblasts in the bone marrow with Prussian blue staining
   

3. X-linked forms of hereditary sideroblastic anemia generally exhibit low activity of ALAS (5-aminolevulinate synthase)

5. Lead poisoning

1. inhibits heme synthesis (delta-ALA dehydratase and ferrochelatase)
2. finger, wrist, foot drop from neurotoxicity
3. gingival lead lines can be seen
4. tx with EDTA

6. Sickle cell disease

1. structurally abnormal hemoglobin (point mutation Val->Glutamic acid)
2. primarily seen in African-Americans
3. sickle cell crisis: deformed RBCs clog blood vessels (very painful), leads to organ infarction (autosplenectomy), strokes
   
4. susceptible to encapsulated bacteria (S. pneumo, H. flu, N. meningitis) and Salmonella for osteomyelitis

Anemia: any condition in which the number of red blood cells, the amount of hemoglobin (protein in RBCs), and the volume of packed red blood cells in the blood are lower than normal levels

Hemoglobin: an iron-containing protein pigment occurring in the red blood cells and functioning primarily in the transport of oxygen from the lungs to the body tissues.

Iron Absorption

1. Dietary or supplemental iron enters the stomach.

2. Iron is oxidized to the Fe3+ (insoluble).

3. Intestinal mucosal cells in the duodenum and upper jejunum absorb the iron.

4. The iron is coupled to transferrin (Tf) in the circulation which delivers it to the cells of the body.

Gastric acidity as well as ascorbate prevents precipitation of the normally insoluble Fe³⁺. Phytates, tannins and antacids block iron absorption.

• Enterobacteriaceae (=enteric gram-negative rods, enteric bacteria, coliform bacteria): a large, heterogeneous group of gram-negative rods
• Natural habitat is the intestinal tract of humans and animals
• Some enteric organisms (E.coli) are part of the normal flora and incidentally cause disease, while others (salmonellae, shigellae) are regularly pathogenic for human

Classification

More than 25 genera and 110 species

Clinically signifiacnt Enterobacteriaceae: 20-25 species

1. Morphology & Identification

A. Culture & Gram staining

B. Growth characteristics

• Culture on differential media, complex media: Table
  

2. Antigenic Structure

1) O antigens: The most external component of the lipopolysaccharide (LPS) of gram (-) bacteria. Differ from organism to organism, depending on different sugars and different side-chain substitutions. More than 150 different heat stable somatic O antigens.

2) K antigens: more than 100 heat-labile K (capsular, Kapsule) Ags

3) H antigens: more than 50 H (flagellar) Ags

* Vi antigens: the capsular Ags in Salmonella Typhi

2 type of diseases

1) Diarrhea

2) Various other infections: urinary tract infection (UTI), pneumonia, bacteremia, and sepsis, especially in debilitated hospitalized patients

1. Diarrhea

1) Background

- Intestinal tract facilitates huge fluxes of water: About 9 L of fluid enter the adult upper intestinal tract each day, however fecal water content is typically less than 200 mL/day

- The majority of this fluid is absorbed in the small intestine

2) Mechanisms of bacteria cause disease in the intestinal tract

- Clinical manifestations depending on the "depth" of intestinal invasion

Associated with antral gastritis, duodenal (peptic) ulcer, and possibly gastric ulcers and carcinomas

1. Morphology and Identification

• Spiral-shaped gram-negative rod with multiple flagella at one pole
• grows in 3-6 d at 37 ℃ in a microaerophilic environment as for C jejuni
• Skirrow's medium with vancomycin, polymyxin B, and trimethoprim, chocolate medium, other selective media with antibiotics
• A strong producer of urease -> ammonia production

2. Pathogenesis and Clinical Findings

• Grows optimally at a pH of 6.0-7.0.

How can H.pylori grow in stomach?

1) Deep in the mucus layer near the epithelial surface

On the lumen side of the mucus, the pH is low (1.0-2.0) while on the epithelial side the pH is about 7.4

2) produce Protease modifies the mucus and reduces the ability of acid to diffuse.

3) produce Urease yields production of ammonia and further buffering of acid.

• Acute infection: nause and pain, vomiting and fever, last for less than 1-2 week
• Once colonized, persists for years and perhaps decades or even a lifetime

4. Diagnostic Laboratory Tests

• Gastroscopy procedure with biopsy, Giemsa or silver stains can show the organisms.
• The sensitivity and specificity of histologic analysis approach 100%

Urease Test

• the most rapid way to detect H. pylori
• The abundance of urease produced by the organism permits detection of the alkaline byproduct in less than 2 hours: biopsy material + urea containing medium -> shift in pH -> color change
• Sensitivity: 75-95%, Specificity: 100%

5. Treatment

Triple therapy of antibiotics (metronidazole + bismuth subsalicylate or bismuth subcitrate + amoxicillin or tetracycline) + proton pump inhibitor (e.g., omeprazole) for 14 days -> eradication rate > 90% ofH. pylori and the greatest success in curing gastitis or peptic ulcer disease

6. Epidemiology & Control

• Infections are common, particularly in people in a low socioeconomic class or in developing nations
• <> 80% in adults
• Humans are the primary reservoir, an animal reservoir has not been identified
• person-to-person transmission (fecal to oral)

Campylobacter jejuni, ETEC, and the Rotavirus are the three most common causes of diarrhea in the world

1. Morphology and Identification

Gram (-) rods with comma, S or "gull-wing" shapes with a single polar flagellum.

2. The culture characteristics are most important.

Incubation atmosphere ; reduced O2 (5%) with added CO2 (10%).

Incubation should be at 42-43 ℃ to prohibit other bacterial growth

Selective media : Skirrow's medium with vancomycin, polymyxin B, and trimethoprim

3. Pathogenesis and Clinical Findings

• Acquired by oral route (from food, drink, contact with infected animals, or animal products)
• Infective dose : 10⁴ organisms
• Multiply in small intestine, invade the epithelium, produce inflammation that result in the appearance of red and white blood cells in the stools
• Begin with a prodrome of fever and headache, followed after half a day by abdominal cramps and profuse diarrhea that may be grossly bloody
• Self-limited (5-8 days)

There is an aspect of cardiac function that is not as intuitively obvious and not as well understood as the systolic function of the heart; that is the diastolic function of the heart. If the heart does not squeeze well and does not pump a lot of blood the cardiac output goes down. What happens during the filling phase of the heart is crucially important as well. This determines a lot of the symptomatology of people who have impaired cardiac function.

1. PRELOAD - The same phenomenon we discussed when we talked about the determinants of the change of length in the muscle fiber (lecture 1)applies to the heart as a whole. Fiber length was defined earlier as the preload of a muscle strip. If you integrate fiber length or muscle strip length over the entire three dimensional structure of the heart, you get volume. As you increase the volume of a chamber passively during diastole, the pressure within the chamber increases, (diastolic pressure). Think of a balloon that is being blown up. The more air you force into that balloon, the greater the pressure within that balloon and the greater the tension in the wall of the balloon. As the diastolic volume increases in a cardiac chamber the diastolic pressure increases. Clinically and practically it is pretty easy to measure the pressure within the heart. Pressure correlates with stretch and volume. Therefore end diastolic pressure is used as a stand-in for preload because it is easier to measure and because of its unique correlation between volume and pressure for any given heart at any moment in time.

2. AFTERLOAD - In terms of a muscle strip is the force against which it is shortening. In the case of the intact heart (left ventricle) the force that the individual fibers are generating as they contract converts into blood pressure or aortic pressure. Aortic pressure is often used as a stand-in for afterload. We will see that there are ways of altering that force, (that wall tension), in systole that directly affect the performance of the heart even though the aortic pressure itself may not be altered that much.

3. CONTRACTILITY - The innate property of a muscle is to contract. This can be altered with a variety of inotropic agents, (such as, catecholes, digitalis, phosphodiesterase inhibitors). Why would you do this? Usually this is done because the contractility has been diminished by whatever disease process is going on.

4. HEART RATE - In normal exercise HR is a major determinant of increased CO. This is probably the major compensation that normal individuals use to alter their cardiac output.
   

• is an abnormality of both differentiation and maturation
• dysplasia is a condition of disordered cell growth and proliferation which may arise de novo or from tissues already showing pathological hyperplasia, metaplasia, or chronic irritation and inflammation
• early stage dysplasia- reversible- if the stimulus is removed
• advanced dysplasia can progress to neoplasia- cancer

Most important microscopic features of dysplasia:

• Nuclear abnormalities -
  
• is characterized by increased size of nucleus (absolute and relative to the amount of cytoplasm)- increased nuclear/cytoplasmic ratio
• increased chromatin content
• abnormal chromatin distribution- coarse chromatin, clumping
• nuclear membrane abnormalities- thickening

• Cytoplasmic abnormalities -
• result from failure of normal differentiation, for example lack of mucin secretion (in glandular epithelium), lack of keratinization (in squamous epithelium)

• Increased rate of cell proliferation -
• is characterized by increased number of mitotic figures in many layers of epithelium (in contrast to the normal state in which mitoses are limited to basal and parabasal layers)
• mitoses are morphologically normal
• Disordered maturation -
  
• dysplastic epithelium resemble basal (stem) cells

• Grades of dysplasia - mild-moderate-severe

• epithelial dysplasia is premalignant lesion = lesion associated with higher risk of development of cancer = general term for invasive aggressive malignant tumor with potential to metastasize

Clinical examples of the dysplasia to neoplasia sequence:

1. Benign colorectal polyps (adenomas)- are composed of dysplastic epithelial glands-if left without surgical treatment- the majority of these will turn into malignant tumors
2. dysplasia in the uterine cervical epithelium- changes known as CIN- cervical intraepithelial neoplasia- if not treated- they will develop into maligant tumor
3. atypical hyperplasia, dysplasia and carcinoma- breast, uterine endometrium

The risk of developing the cancer depends on

• grade of dysplasia
• duration of d.
• site of dysplasia (d.in urinary bladder has high risk, d. of uterine cervix lower risk)

Differences between dysplasia and cancer

• differs in two important respects:

1. invasiveness
2. reversibility

• in dysplasia the abnormal cell proliferation does never invade the BM. Complete removal of dysplastic tissue is curative cancer in contrast, invades the BM and spreads through lymphatic and blood vessels, thus excision may not be curative
• reversibility- may sometimes return to normal- unlike cancer which is irreversible

Pathogenic for humans or animals when acquired by the oral route.

Differ from the other enterics because it livess in the GI tracts of animals and transmitted from animals and animal products to humans (S.typhi is an exception as it is not zoonotic, carried only by humans)

Salmonella (like Shigella) is never considered part of the normal flora, it is always pathogenic

1. Antigenic Structure

Possess several O Ags (>60), different H Ags and Vi (just like K, capsular antigen, but salmonella named it Vi: for virulence) Ags

2. Classification ; complex.

3. Pathogenesis & Clinical Findings

Chiefly pathogenic in animals (reservoir for human infection)

Always enter via the oral route (contaminated food or drink); infective dose 10⁵-10⁸, most infections are acquired by eating contaminated food products

Host factors to resistance: gastric acidity, normal intestinal flora, local intestinal immunity.

A. The "Enteric Fevers" (Typhoid Fever):

S. typhi

Small intestine ≫ invade intestinal epithelium ≫ regional lymph node ≫ lymphatics ≫ bloodstream ≫ multiple organ (invasion bacteria are phagocytosed by monocytes and can survive intracellularly)

Incubation period (10-14 days) ≫ abdominal pain with constipation (adult) or mild diarrhea (infant) ≫ hepatosplenomegaly, Fever, malaise, headache, bradycardia, anorexia, loss of weight

: fever rises to a high plateau (41-41 degree C, 4-8 wks prolonged if not treated)

: Rose spots on the skin of the abdomen or chest may be developed in 1st week of infection

Chief complication : intestinal hemorrhage & perforation (mortality rate 10-15% -> less then 1% by treatment)

Some people recovering from typhoid fever become chronic carriers, harboring S. typhi in their gallbladders and excreting the bacteria constantly (about 3%)

B. Bacteremia With Focal Lesions:

S choleraesuis: usually cause systemic dissemination, does not involve the GI tract

Prolonged fever with blood culture positive

The risk is higher in pediatric and geriatric patient and the acquired immunodeficiency syndrome (AIDS)

The clinical presentation of bacteremia is like that of other gram (-) bacteremia but focal lesions in lungs, bones, meninges, etc can occur in as many as 10% of patients

C. Enterocolitis (Formerly "Gastroenteritis"):

Most common form of salmonellosis

Can be caused by any of hundreds of serotypes of Salmonella enteritidis

Incubation period (8-48 hours) ≫ nausea, abdominal pain, vomiting, low-grade fever ≫ spontaneous resolution

4. Diagnosis

Isolation from stool specimens requires use of selective media

Widal test: As least two serum specimens, obtained at intervals of 7-10 days

High titer of antibody to the O antigen >1:160 = active infection

High titer of antibody to the H antigen >1:160 = past immunization or past infection

High titer of antibody to the Vi antigen = carrier

5. Immunity

Infection with Salmonella usually confer certain degree of immunity ≫ reinfection may occur but is often milder than the first infection

6. Treatment

Enteric fever and bacteremia with focal lesions require antimicobial treatment

Enterocolitis does not require antimicrobial treatment

In most carriers, the organisms persist in the gall bladder and in the biliary tract (ampicillin alone or with cholecystectomy)

7. Prevention & Control

Most infections can be controlled by proper preparation of poultry and eggs (completely cooked) and avoidance of contamination of other foods with uncooked poultry products

Vaccination against S.typhi can reduce the risk of disease for travelers into endemic areas

Natural habitat is limited to intestinal tracts of humans and other primates

4 species of Shigella:

nonmotile: no flagella

1. Pathogenesis & Pathology

• limited to the gastrointestinal tracts infections
• Highly communicable (infective dose: 103 organisms)
• Invasion of the mucosal epithelial cells by induced phagocytosis ≫ lyse the phagocytic vacuole and escape from the phagocytic vacuole ≫ multiplication and spread within the epithelial cell cytoplasm ≫ propelled through the cytoplasm to adjacent cells, cell to cell passage ≫ release interleukin-1b by survived infected cell ≫ attraction of WBC ≫ Microabscesses in the wall of the large intestine and terminal ileum ≫ necrosis of the mucous membrane, superficial ulceration, bleeding

2. Toxins

A. Endotoxin : all Shigellae release LPS upon autolysis, irritate the bowel wall.

B. Shigella dysenteriae Exotoxin (Shiga toxin)

• S dysenteriae produce heat-labile exotoxin
• Like the toxin produced by EHEC
• Primary manifestation of toxin activity is the intestinal epithelium
• in a small subset of patients, mediate HUS

3. Clinical Findings

• Gastroenterites (shigellosis)
• Most common form is an initial watery diarrhea progressing within 1 to 2 days to abdominal cramps and tenesmus (with or without bloody stools)
• Asymptomatic carrier develops in a small number of patients (reservoir for future infections)
• A severe form of disease is caused by S. dysenteriae

4. Treatment, Prevention, & Control

• Antibiotic therapy shortens the course of symptomatic disease and fecal shedding
• Transmitted by food, fingers, feces, and flies from person to person
• Most cases are under 10 yrs of age
• Appropriate infection control measure should be instituted to prevent spread of the organism

• associated with variety of disease, including sepsis, UTIs, meningitis, and gastroenteritis.

Many antigens (O,H,K) have been epidemiologic purposes.

1. E. coli-associated diarrheal diseases

• Extremely common worldwide.

1) Enterotoxigenic E coli (ETEC)

Site of action: small intestine, secretory diarrhea

A common cause of "traveler's diarrhea", most common bacterial etiology of acute bacterial diarrhea worldwide.

Produce one or both of two protein toxins

A. Heat-labile exotoxin (LT): just like cholera toxin.

subunit B - attaches to the G_M1 ganglioside and facilitates the entry of subunit A  activates adenylyl cyclase  increase cAMP  prolonged hypersecretion of water and electrolyte imbalance diarrhea

B. Heat-stable enterotoxin (ST) :

ST_a : Activates guanylyl cyclase and stimulate fluid secretion.

ST_b : Stimulates cyclic nucleotide-independent secretion.

2) Enteropathogenic E coli (EPEC)

Site of action: small intestine, secretory diarrhea

Major cause of diarrhea in infants, rare in older children and adults.

Outbreaks of diarrhea in nurseries in developed countries

Bacterial attachment to epithelial cells of the small intestine by chromosomally mediated factor  effacement (destruction) of the microvillus  malabsorption due to microvilli destruction  diarrhea

3) Enteraggregative E coli (EAEC)

Site of action: small intestine, secretory diarrhea

Acute and chronic diarrhea in developing countries

Aggregation on epithelium of the small intestine by aggregative adherence fimbriae I and II which are carried on a plasmid  shortening of the microvilli, mononuclear infiltration  stimulate secretion of mucus, malabsorption  diarrhea

4) Enterohemorrhagic E coli (EHEC)

Site of action: large intestine, inflammatory diarrhea

Secrete the powerful Shiga-like toxin (verotoxin)

Verotoxin ; same mechanism of action as the Shigella toxin

Inhibit protein synthesis by inhibiting the 60S ribosome  intestinal cell death  bloody diarrhea (hemorrhagic), abdominal cramps

Hemolytic uremic syndrome (HUS, acute renal failure (uremia), microangiopathic hemolytic anemia, thrombocytopenia) is associated with a strain of EHEC, called E.coli O157:H7

Prevent by thorough cooking of ground beef

5) Enteroinvasive E coli (EIEC)

Site of action: large intestine, inflammatory diarrhea

The virulence factor encoded by plasmid mediated invasion to the epithelial cells --> host tries to get rid of the invading bacteria --> immune mediated inflammatory reaction with fever

organism	Enteric syndrome	site of infection	Bloody stools	Fecal WBC	pathogenic Mx	Extraintestinal manifestation
EIEC	inflammatory	Colon	+	++	Invasion & inflammation	rare
EHEC
			++	0	Epithelial effacement & verotoxin	HUS, thrombocytopenic purpura

Treatment

No single specific therapy is available

Epidemiology, Prevention, & Control

Most infections are endogenous (patient's normal microbial flora)

Strains causing gastroenteritis are generally acquired exogenously

Infections are controlled by use of appropriate infection-control practices to reduce the risk of nosocomial infections (e.g., restricting use of antibiotics, avoiding unnecessary use of urinary tract catheters)

Maintenance of high hygienic standards to reduce the risk of exposure to gastroenteritis strains

Proper cooking of beef products to reduce risk of EHEC infections

V parahaemolyticus : acute gastroenteritis by contaminated seafood (raw fish or shellfish) 》subside spontaneously in 1-4 days with no treatment

V vulnificus : severe wound infections, bacteremia & probably gastroenteritis

• Apt to be found in oysters, especially in warm months
• Bacteremia with no focus of infection by infected oysters and with alcoholism or liver disease Infection often proceeds rapidly (50% of mortality rate).
• Tetracycline, or ciprofloxacin

1. Morphology and Identification

• Comma-shaped, curved rod with a polar flagellum
• Oxidase-positive
• Rapidly killed by acid & grow at a very high pH (8.5-9.5)
• Halotolerant or halophilic : grows on media containing 6% NaCl

2. Antigenic Structure

• A single heat-labile flagella H antigen
• O lipopolysaccharides : serologic specificity
• V cholerae serogroups O1 and O139; classic cholera (Table 18-1)
• V cholerae serogroups non-O1 and non-O139 ; Cholera-like diarrhea

3. Vibrio cholerae Enterotoxin

Produce a heat-labile enterotoxin (Subunits A and B); chromosomal control (the same mechnism of action as E.coli's LT toxin, but LT is transmitted via s plasmid)

binding to Ganglioside GM1 on intestinal epithelium by subunit B ≫ entry of the A subunit ≫ Subunit A activate G-protein ≫ stimulate the activity of a membrane-bound adenylate cyclase ≫ production intracellular cAMP ≫ secretion of Na and Cl and inhibition of Na and Cl reabsorption ≫ prolonged hypersecretion of water and electrolytes ≫ diarrhea (20-30 L/d) ≫ dehydration

4. Pathogenesis & Clinical Findings

• Infective dose: 108-1010 organisms
• Not an invasive infection
• About 60% of infection with classic V Cholerae: Asymptomatic
• Incubation period (1-4 days) ≫ Sudden onset of nausea and vomiting, profuse diarrhea with abdominal cramps, rice-water like stool (mucus, epithelial cells, large numbers of vibrios) ≫ profound dehydration, circulatory collapse and anuria, mortality rate without treatment is 25-50%

5. Immunity ; Partial immunity to reinfection

• some protection by gastric acid

6. Treatment

• Water and electrolyte replacement & oral tetracycline.

7. Epidemiology, Prevention & Control

• Endemic in India and Southeast Asia
• Spread by person-to-person and by water, food, and flies.
• Control: education and improvement of sanitation, particularly of food and water
• Chemoprophylaxis, and repeated injection of a vaccine: limited protection to heavily exposed persons

Accessory cell: Cell required for, but not actually mediating, a specific immune response. Often used to describe antigen-presenting cells (APC; see below).

Affinity: A measure of the binding constant of a single antigen combining site with a monovalent antigenic determinant.

Agglutination: The aggregation of particulate antigen by antibodies. Agglutination applies to red blood cells as well as to bacteria and inert particles covered with antigen.

Allelic: Relating to one of a series of two or more alternate forms of a gene that occupy the same position or locus on a specific chromosome.

Allelic exclusion: The ability of heterozygous lymphoid cells to produce only one allelic form of antigen-specific receptor when they have the genetic endowment to produce both. Genes other than those for the specific receptors are usually expressed codominantly.

Allergen: An antigen responsible for producing allergic reactions by inducing IgE formation.

Allergy: A term covering immune reactions to non-pathogenic antigens, which lead to inflammation and deleterious effects in the host.

Allogeneic: Having a genetic dissimilarity within the same species.

Allograft: A tissue transplant (graft) between two genetically nonidentical members of a species.

Allotypes: Antigenic determinants that are present in allelic (alternate) forms. When used in association with immunoglobulin, allotypes describe allelic variants of immunoglobulins detected by antibodies raised between members of the same species.

Alternate (Alternative) pathway: The mechanism of complement activation that does not involve activation of the C1, C4, C2 pathway by antigen-antibody complexes, and begins with the activation of C3.

Anaphylatoxin: Substance capable of releasing histamine from mast cells.

Anaphylaxis: Immediate hypersensitivity response to antigenic challenge, mediated by IgE and mast cells. It is a life-threatening allergic reaction, caused by the release of pharmacologically active agents.

Antibody: Serum protein formed in response to immunization; antibodies are generally defined in terms of their specific binding to the immunizing antigen.

Antibody-dependent, cell-mediated cytotoxicity (ADCC): A phenomenon in which target cells, coated with antibody, are destroyed by specialized killer cells (NK cells and macrophages), which bear receptors for the Fc portion of the coating antibody (Fc receptors). These receptors allow the killer cells to bind to the anti-body-coated target.

Antigen: Any foreign material that is specifically bound by specific antibody or specific lymphocytes; also used loosely to describe materials used for immunization. Antigens may also be immunogens if they are able to trigger an immune response, or haptens if not.

Antigen-binding site: The part of an immunoglobulin molecule that binds antigen specifically.

Antigen-presenting cell (APC): A specialized type of cell, bearing cell surface class II MHC (major histocompatibility complex) molecules, involved in processing and presentation of antigen to inducer, or helper , T cells. Examples: macrophage, dendritic cells.

Antigen receptor: The specific antigen-binding receptor on T or B lymphocytes; these receptors are transcribed and translated from rearrangements of V genes.

Antigenic determinant: A single antigenic site or epitope on a complex antigenic molecule or particle.

Antigen processing: Large molecules are broken down (processed) within macrophages into peptides and presented within the groove of MHC molecules.

Atopy: A term used by allergists to describe IgE-mediated anaphylactic responses in humans, usually genetically determined.

Autograft: A tissue transplant from one area to another on a single individual.

Autoimmunity (autoallergy): An immune response to "self" tissues or components. Such an immune response may have pathological consequences leading to autoimmune diseases.

Avidity: The summation of multiple affinities, for example when a polyvalent antibody binds to a polyvalent antigen.

B lymphocyte (B cell): The precursors of antibody-forming plasma cells; these cells carry immunoglobulin and class II MHC (major histocompatibility complex) antigens on their surfaces.

Basophil: A polymorphonuclear leukocyte., whose basophils granules contain heparin, histamine and other vasoactive amines. Within tissues, these cells are known as mast cells q.v.

Bence-Jones protein: Dimers of immunoglobulin light chains in the urine of patients with multiple myeloma.

Blocking antibody: A functional term for an antibody molecule capable of blocking the interaction of antigen with other antibodies or with cells.

Bursa of Fabricius: An outpouching of the cloaca in birds; site of development of B cells in birds.

Carcinoembryonic antigen (CEA): Antigen present during embryonic development which normally disappears but reappears in malignant tissue.

Carrier: A large immunogenic molecule or particle to which an antigenic determinant is attached, allowing the determinant to become immunogenic.

Cell-mediated cytotoxicity (CMC): Killing (lysis) of a target cell by an effector lymphocyte.

Cell-mediated immunity (CMI): Immune reaction mediated by T cells; in contrast to humoral immunity, which is antibody mediated. Also referred to as delayed-type hypersensitivity.

Chemotaxis: Migration of cells along a concentration gradient of an attractant.

Class I, II and III MHC molecules: Proteins encoded by genes in the major histocompatibility complex (q.v.). Class I molecules are designated HLA-A, B, or C. Class II molecules are designated DP, DQ or DR.

Class switch: See isotype switch.

Classical pathway: The mechanism of complement activation initiated by antigen-antibody aggregates and proceeding by way of C1, C4 and C2.

Clonal deletion: The loss of lymphocytes of a particular specificity due to contact with either "self" or artificially introduced antigen.

Clonal selection theory: The prevalent concept that specificity and diversity of an immune response are the result of selection by antigen of specifically reactive clones from a large repertoire of preformed lymphocytes, each with individual specificities.

Cluster determinant (CD): Cluster of antigens with which antibodies react that characterize a cell surface marker.

Combinatorial joining: The joining of segments of DNA to generate essentially new genetic information, as occurs with Ig genes during the development of B cells. Combinatorial joining allows multiple opportunities for 2 sets of genes to combine in different ways.

Complement: A series of serum proteins involved in the mediation of immune reactions. The complement cascade is triggered classically by the interaction of antibody with specific antigen.

Complement components: An enzymatic system of serum proteins triggered by the classical and alternative pathways, and resulting in target cell lysis, phagocytosis, opsonization and chemotaxis.

Complement receptor: A structure found on erythrocytes, lymphocytes, neutrophils, monocytes and macrophages that binds C3 fragments.

Constant region (C region): The invariant carboxyl-terminal portion of an antibody molecule, as distinct from the variable region which is at the amino-terminal of the chain.

Coombs' test: A test named for its originator, R.R.A. Coombs, used to detect non-agglutinating antibodies on red blood cells by addition of an anti-immunoglobulin antibody.

Cross-reactivity: The ability of an antibody, specific for one antigen, to react with a second antigen; a measure of relatedness between two different antigenic substances.

Cytokines: Soluble substances secreted by cells, which have a variety of effects on other cells, e.g. Interleukin 1 (Il-1).

Cytotoxic (Cytolytic) T cell: Cell that kills target cells bearing appropriate antigen within the groove of an MHC class I molecule that is identical to that of the T cell.

D gene: A small segment of immunoglobulin heavy-chain and T-cell receptor DNA, coding for the third hypervariable region of most receptors.

Delayed type hypersensitivity (DTH): A T cell-mediated reaction to antigen, which takes 24-48 hours to develop fully, and which involves release of lymphokines and recruitment of monocytes and macrophages. Also called c cell-mediated immunity.

Determinant: Part of the antigen molecule which binds to an antibody-combining site or to a receptor on T cells (see hapten and epitope).

Differentiation antigen: A cell surface antigenic determinant found only on cells of a certain lineage and at a particular developmental stage; used as an immunologic marker.

Domain: A compact segment of an immunoglobulin molecule, made up of about 110 amino acids around an S-S bond, and encoded by a unique segment of DNA, surrounded by nontranslated sequences.

DR antigens: MHC class II molecules found on B cells and antigen-presenting cells of humans.

Enchancing antibodies: Antibodies which enhance the survival of a graft or of a tumour.

Enzyme-linked immunosorbent assay (ELISA): An assay in which an enzyme is linked to an antibody and a coloured substrate is used to measure the activity of bound enzyme and, hence, the amount of bound antibody.

Eosinophil: A polymorphonuclear leukocyte with large eosinophilic (i.e. red) cytoplasmic granules.

Eosinophil chemotactic factor of anaphylaxis (ECF-A): A substrate released from mast cells during anaphylaxis which attracts eosinophils.

Epitope: An alternative term for antigenic determinant.

Equivalence zone: In a precipitin reaction, the region in which the concentration of antigen and antibody leads to maximal precipitation.

Exon: The region of DNA coding for a protein or a segment of a protein.

Fab: Fragment of antibody containing the antigen-binding site, generated by cleavage of the antibody with the enzyme papain, which cuts at the hinge region N-terminally to the inter-H-chain disulphide bond and generates two Fab fragments from one antibody molecule.

F(ab')2: A fragment of an antibody containing two antigen-binding sites generated by cleavage of the antibody molecule with the enzyme pepsin which cuts at the hinge region C-terminally to the inter-H-chain disulphide bond.

Fc: Fragment of antibody without antigen-binding sites, generated by cleavage with papain; the Fc fragment contains the C-terminal domains of the heavy immunoglobulin chains.

Fc receptor (FcR): A receptor on a cell surface with specific binding affinity for the Fc portion of an antibody molecule. Fc receptors are found on many types of cells.

Fluorescent antibody: An antibody coupled with a fluorescent dye, used with a fluorescence microscope to detect antigen on cells, tissues, or microorganisms.

Freund's complete adjuvant: A water-in-oil emulsion that contains an immunogen, an emulsifying agent, and killed mycobacteria which enhance the immune response to the immunogen; termed "incomplete" Freund's adjuvant if mycobacteria are not included.

Genotype: All of the genes possessed by an individual; in practice it refers to the particular alleles present at the loci in question.

Germ line: Refers to genes in germ cells as opposed to somatic cells, that is, genes in their unrearranged state rather than those rearranged for production of a protein.

Graft versus host reaction (GVH): The pathologic consequences of a response initiated by transplanted immunocompetent T lymphocytes into an allogeneic, immunologically incompetent host. The host is unable to reject the grafted T cells and becomes their target.

HLA complex: See 'Major histocompatibility complex'.

H-2 complex: The major histocompatibility complex situated on chromosome 17 of the mouse; contains subregions K, I and D.

Haplotype: A particular combination of closely linked genes on a chromosome inherited from one patient.

Hapten: A compound, usually of low molecular weight, that is not itself immunogenic but that, after conjugation to a carrier protein or cells, becomes immunogenic and induces antibody, which can bind the hapten alone in the absence of carrier.

Heavy chain (H chain): The larger of the two types of chains that comprise a normal immunoglobulin or antibody molecule.

Helper T cells: A class of T cells which help trigger B cells to make antibody against thymus-dependent antigens. Helper T cells also help generate cytotoxic T cells.

Heterophile antigen: A cross-reacting antigen that appears in widely ranging species such as humans and bacteria.

Hinge region: A flexible, open segment of an antibody molecule that allows bending of the molecule. The hinge region is located between Fab and Fc and is susceptible to enzymatic cleavage.

Histocompatibility: Literally, the ability of tissues to get along; in immunology, it means identity in all transplantation antigens. These antigens, in turn, are collectively referred to as histocompatibility antigens.

Humoral immunity: Any immune reaction that can be transferred with immune serum is termed humoral immunity (as opposed to cell-mediated immunity). In general, this term refers to resistance that results from the presence of specific antibody.

Hybridoma: A hybrid cell that results from the fusion of an antibody-secreting cell with a malignant cell; the progeny secrete antibody without stimulation and proliferate continuously both in vivo and in vitro.

Hypersensitivity: State of reactivity to antigen that is greater than normal for the antigenic challenge; hypersensitivity is the same as allergy and denotes a deleterious outcome rather than a protective one.

Hypervariable regions: Portions of the light and heavy immunoglobulin chains that are highly variable in amino acid sequence from one immunoglobulin molecule to another, and that, together, constitute the antigen-binding site of an antibody molecule. Also, portions of the T-cell receptor which constitute the antigen-binding site.

Ia: "Immune response-associated" proteins, found on B cells and antigen-presenting cells of mice; an old term now replaced with MHC (major histocompatibility complex) class II molecules.

Idiotype: The combined antigenic determinants (idiotopes) found on antibodies of an individual that are directed at a particular antigen; such antigenic determinants are found only in the variable region.

Immediate-type hypersensitivity: Hypersensitivity tissue reaction occurring within minutes after the interaction of antigen and antibody.

Immune adherence: The adherence of particulate antigen coated with C3b to tissue having cells with C3b receptors.

Immune complex: Antigen bound to antibody.

Immune modulators: Substances that control the expression of the immune response.

Immune response (Ir) gene: A gene controlling an immune response to a particular antigen; most genes of this type are in the MHC (major histocompatibility complex), and the term is rarely used to describe other types of Ir genes outside the MHC.

Immunogen: A substance capable of inducing an immune response (as well as reacting with the products of an immune response). Compare with antigen.

Immunoglobulin (Ig): A general term for all antibody molecules. Each Ig unit is made up of two heavy chains and two light chains and has two antigen- binding sites.

Interferon: A group of proteins having antiviral activity and capable of enhancing and modifying the immune response.

Interleukins: Glycoproteins secreted by a variety of leukocytes which have effects on other leukocytes.

Internal image: A spatial configuration of the combining site of an anti-idiotype antibody which resembles the epitope to which the idiotype is directed.

Intron: A segment of DNA that does not code for protein; the intervening sequence of nucleotides between coding sequences or exons.

Isograft: A tissue transplanted between two genetically identical individuals.

Isohemagglutinins: Antibodies to major red blood cell antigens present normally as a result of inapparent immunization by cross-reactive antigens in bacteria, food, etc.

Isotypes: Classes of antibody that differ in the constant region of their heavy chain (Fc portion); distinguishable also on the basis of reaction with antisera raised in another species. These differences also result in different biological activities of the antibodies.

Isotype switch: The shift of a B cell or its progeny from the secretion of antibody of one isotype or class of antibody with the same V regions but a different heavy- chain constant region and, hence, a different isotype (class switch).

J chain (joining chain): A polypeptide involved in the polymerization of immunoglobulin molecules IgM and IgA.

J gene: A gene segment coding for the J or joining segment in immunoglobulin DNA; V genes translocate to J segments in L chains, and to D and J segments in H chains. Also, codes for a portion of the T-cell receptor.

K cell: An effector lymphocyte with Fc receptors which allow it to bind to and kill antibody-coated target cells.

Killer T cell: A T cell with a particular immune specificity and an endogenously produced receptor for antigen, capable of specifically killing its target cell after attachment to the target cell by this receptor. Also called cytotoxic T cell.

Light chain (L chain): The light chain of immunoglobulin is a structural feature that occurs in two forms: kappa and lambda.

Linkage disequilibrium: The frequency, in a population of linked genes, which is governed by factors other than change.

Lymphocyte: Small cell with virtually no cytoplasm, found in blood, in all tissue, and in lymphoid organs, such as lymph nodes, spleen, and Peyer's patches, and bears antigen-specific receptors.

Lymphokines: Soluble substances secreted by lymphocytes, which have a variety of effects on lymphocytes and other cell types.

Macrophage: A large phagocytic cell of the mononuclear series found within tissues. Properties include phagocytosis, and antigen presentation to T cells.

Macrophage-activating factor (MAF): Actually several lymphokines, including interferon, released by activated T cells, which together induce activation of macrophages, making them more efficient in phagocytosis and cytotoxicity.

Major histocompatibility complex (MHC): A cluster of genes on chromosome 6 in humans, encoding cell surface molecules that are polymorphic and that code for antigens which lead to rapid graft rejection between members of a single species which differ at these loci. Several classes of protein such as MHC class I and II proteins are encoded in this region. These in humans, are known as 'Human leukocyte antigens' (HLA).

Mast cell: Tissue located cell probably derived from basophils. Possesses receptor for Fc of IgE. Participates in 'Immediate hypersensitivity' reactions.

Memory: In the immune system, memory denotes an active state of immunity to a specific antigen, such that a second encounter with that antigen leads to a larger and more rapid response.

MHC class I molecule: A molecule encoded to genes of the MHC which participates in antigen presentation to cytotoxic T (CD8+) cells.

MHC class II molecule: A molecule encoded by genes of the MHC which participates in antigen presentation to helper T (CD4+) cells.

MHC restriction: The ability of T lymphocytes to respond only when they 'see' the appropriate antigen in association with "self" MHC class I or class II proteins on the antigen presenting cells.

Migration inhibition factor (MIF): A lymphokine that inhibits the motility of macrophages in culture.

Minor histocompatibility antigens: These antigens, encoded outside the MHC, are numerous, but do not generate rapid graft rejection or primary responses of T cells in vitro. They do not serve as restricting elements in cell interactions.

Mitogen: A substance that stimulates the proliferation of many different clones of lymphocytes.

Mixed lymphocyte reaction (MLR): When lymphocytes from two individuals are cultured together, a proliferative response is generally observed, as the result of reactions of T cells of one individual to MHC antigens on the other individual's cells.

Monoclonal: Literally, coming from a single clone. A clone is the progeny of a single cell. In immunology, monoclonal generally describes a preparation of antibody that is monogenous, or cells of a single specificity.

Monocyte: Large circulating white cell, 2-10% of total white cells, phagocytic, indented nucleus. Migrates to tissues, where it is known as a macrophage.

Monokines: Soluble substances secreted by monocytes, which have a variety of effects on other cells.

Myeloma: A tumour of plasma cells, generally secreting a single species of immunoglobulin.

NK cell: Naturally occurring, large, granular, lymphocyte-like killer cells that kill various tumour cells; they may play a role in resistance to tumours. Also, they participate in ADCC. They do not exhibit antigenic specificity, and their number does not increase by immunization.

Null cells: An early population of lymphocytes bearing neither T-cell nor B-cell differentiation antigens.

Opsonin: A substance, usually antibody or complement component, which coats a particle such as a bacterium and enhances phagocytosis by phagocytic cells.

Opsonization: Literally means "preparation for eating". The coating of a bacterium with antibody and/or complement that leads to enhanced phagocytosis of the bacterium by phagocytic cells.

Paratope: An antibody combining site that is complementary to an epitope.

Passive immunization: Immunization by the administration of preformed antibody into a nonimmune individual.

Phagocytosis: The engulfment of a particle or a microorganism by leukocytes.

Phenotype: The physical expression of an individual's genotype.

Pinocytosis: Ingestion of liquid or very small particles by vesicle formation in a cell.

Plasma cell: End-stage differentiation of a B cell to an antibody-producing cell.

Polyclonal activator: A substance that induces activation of many individual clones of either T or B cells. See Mitogen.

Polymorphism: Literally, "having many shapes"; in genetics polymorphism means occurring in more than one form within a species; the existence of multiple alleles at a particular genetic locus.

Polymorphonuclear leukocyte: White cell, granular cytoplasm. Neutral staining (neutrophil) - most frequent, phagocytic. Basophilic staining - basophil q.v. Eosinophilic staining - eosinophil q.v.

Primary lymphoid organs: Organs in which the maturation of T and B lymphocytes take place and antigen-specific receptors are first acquired.

Primary responses: The immune response to a first encounter with antigen. The primary response is generally small, has a long induction phase or lag period, consists primarily of IgM antibodies, and generates immunologic memory.

Prophylaxis: Protection.

Radioallergosorbent test (RAST): A solid-phase radioimmunoassay for detecting IgE antibody specific for a particular allergen.

Radioimmunoassay (RIA): A widely used technique for measurement of primary antigen-antibody interactions, and for the determination of the level of important biological substances in mixed samples. It takes advantage of the specificity of the antigen-antibody interaction and the sensitivity that derives from measurement of radioactively labelled materials.

Reagin: Allergist's term for IgE antibodies.

Respiratory burst: Oxygen dependent increase in metabolic activity within phagocytic cells stimulated by bacteria or parasites, to be microbicidal.

Reticuloendothelial system: A network of phagocytic cells.

Rheumatoid factor: An autoantibody (usually IgM) which reacts with the individual's own IgG. Present in rheumatoid arthritis.

Second set rejection: Accelerated rejection of an allograft in an already immune recipient.

Secondary lymphoid organs: Organs in which antigen-driven proliferation and differentiation of B and T lymphocytes takes place.

Secretory component: A surface receptor on epithelial cells lining mucosal surfaces which binds dimeric IgA and transports it through the cell into mucosal secretions.

Serum sickness: A hypersensitivity reaction consisting of fever, rashes, joint pain and glomerulonephritis, resulting from localization of circulating, soluble, antigen-antibody complexes, which induce inflammatory reactions. Serum sickness was originally induced following therapy with large doses of antibody from a foreign source - e.g. horse serum.

Slow-reacting substance of anaphylaxis (SRS-A): A group of leukotrienes released by mast cells during anaphylaxis which induces a prolonged constriction of smooth muscle. This prolonged constriction is not reversible by treatment with antihistamines.

Suppression: A mechanism for producing a specific state of immunologic unresponsiveness by the induction of suppressor T cells. This type of unresponsiveness is passively transferable by suppressor T cells or their soluble products.

Syngeneic: Literally, genetically identical.

Syngraft: Same as isograft.

T cell: A lymphocyte which undergoes a developmental stage in the thymus.

T-dependent antigen: An immunogen that is able to induce antibody synthesis only in the presence of lymphokines released by helper T cells.

T-independent antigen: An immunogen which induces antibody synthesis in the absence of lymphokines released by T cells; the antibodies are generally only of the IgM isotype.

Titre: The reciprocal of the last dilution of a titration giving a measurable effect; e.g. if the last dilution giving significant agglutination is 1:128, the titre is 128.

Tolerance: Diminished or absent capacity to make a specific response to an antigen, usually produced as a result of contact with that antigen under nonimmunizing conditions.

Toxoid: A nontoxic derivative of a toxin used as an immunogen for the induction of antibodies capable of cross-reacting with the toxin.

Unresponsiveness: Inability to respond to antigenic stimulus. Unresponsiveness may be specific for a particular antigen (see tolerance), or broadly nonspecific as a result of damage to the entire immune system, for example after whole body irradiation.