ROSS University SOM - Mini 2

An antigen is a molecule that is recognized by the immune system; a substance (usually foreign) that induces an immune response.

Immunogens are antigens that provoke an immune response. All immunogens are antigens. But not all antigens are immunogens.

Haptens are small molecules that, on their own, are not immunogenic. Antibodies can bind, but binding is below threshold of driving an immune response. Haptens generally only have one epitope. To make a hapten immunogenic, you must conjugate it to a carrier.

A good antigens is one in size range of 10,000 daltons, preferably be a protein, soluble, have some level of foreignness.

Immunogenicity can be impacted.....
Dosage amount --- very small quantities may get rapidly cleared, whereas very large quantities may inhibit response.
Route --- entry of host for most pathogens by crossing mucosal surface.
Host Factors - MHC (they present peptides to T cells).
Adjuvant Activity --- chemical substances that enhance the immune response to an antigen
Human MHC gene Isotypes ---

Epitope is the portion of antigen that binds the antigen recognition molecule --- part of the antigen recognized by antibody or peptide recognized by the T cell receptor.

Since T-cells only recognize peptides -- their epitopes are linear epitopes.

However a B-cell can recognize an epitope linearly or conformationally (secondary or tertiary structure).

Antibodies are at work and play even before we can detect them.

Catabolic Decay Phase = antigen processing, presentation
Immune Elimination PHase = antibodies produced, but not yet detectable
Detectable Antigen-specific Antibody = antibodies detectable even though they've have been at work for a long time.

Made up of 4 chains; two identical heavy chains and two identical light chains.

The variable region (the distal end) is where the gene recombination occurs --- that's where the antigen interacts with the antibody! No rearrangement occurs in the constant region. Greatest variability occurs in the hypervariable regions (loops that occur at the distal most region)

Shape of the Ab can be variable to accommodate spacing of epitopes on pathogen surface.

Papain: Cleaves at the hinge region.

Pepsin: Cleaves below the hinge region keeping it intact but degrades the distal portion of the Fc region.

Through these experiments, it was determined that the Fc (constant) is what determines the function of the Ab and the tissue distribution. It was also determined that the Fab (antibody) region is mediated the antibody binding.

Idiotypic Variation - variations in variable region, particularly hypervariableregion.
Idiotype = specificity

Allotypic Difference = Genetic differences involving different alleles (doesn't make any kind of functional difference)

Isotypic Difference = There are multiple different constant region genes, they encode different classes of antibodies (IgE, IgG, IgM, IgA, IgD).
Isotype = Class - defines function

*IgM = first antibody secreted in immune response. Found on surface of naive B cells. Secreted as a pentamer (10 antigen binding sites). Readily activates classical complement. Found only in blood.

*IgG is the second antibody to be secreted. Secreted in large amount. Most abundant isotype in blood and lymph. Secreted as a monomer. It can activate classical complement, opsonization of pathogens, and neutralization. Found in blood and can cross placenta

Opsonization - Fc receptors (on phagocytic cell) allow recognition of the Fc portion of antibodies.

*IgA = secrete as a monomer and as a dimer. Dimeric form contains J chain and secretory component. Secretory component facilitates transport across epithelium into secretions. Most predominant isotype produced in gut. Main function: neutralization.

*IgE = secreted as monomer. Binds with high affinity to Fc-epsilon receptors on mast cells, eosinophils and basophils. Efficiently trigger degranulation. When the Fc portion of IgE bound to antigen binds to the Fc-epsilon receptor of the mast cell or eosinophil --- it trigger the release of MASSIVE AMOUNTS of granule contents.

*IgD = expressed on surface of naive B cells. Secreted form has no known function.

Anemia is a reduction in total circulating red cell mass below normal limits affecting tissue oxygenation.

On basis of etiology (causes of anemia): blood loss, impaired production, increased destruction.

Increased Blood Loss
Acute - trauma
Chronic (IRON DEFICIENCY ANEMIA)- 1) Gastro-intestinal GI tract diseases (colon cancer, bleeding peptic ulcer)
2) Urinary tract diseases or disorders (stones, bladder cancer)
3) Heavy Bleeding Women Gynecological disturbances (dysfunctional uterine bleeding, liomyoma (fibroids), endometrial carcinoma

Impaired RBC Production
Nutritional Deficiencies - 1) Defective DNA Synthesis (Vitamin B12 or Cobalamine deficiency, Folate deficiency)
2) Defective Hemoglobin Synthesis (Iron deficiency)
3) Erythropoietin Deficiency - Anemia of Chronic Disease (most common anemia in hospitalized patients). Chronic Renal Failure (due to damaged kidneys (EPO production).
4) Inherited Genetic Defects - Defect in Stem Cell Depletion (Fanconi anemia). Defect Affecting Erythroblast Maturation (Thalassemia)
5) Inflammation - induced iron sequestration - Anemia of Chronic Disease (Fe not transferred from storage pool to erythroid precursors in bone marrow, affects Hepcidin (Fe-regulating hormone)
6) Primary Hematopoietic Neoplasms - Acute Leukemias - Acute Lymphoblastic (ALL) & Acute Myeloblastic (AML)
7) Space Occupying Marrow Lesions (Something is in the place of the medully cavity where normal blood production would occur) - Metastatic neoplasm. Granulomatous disease.
8) Infection of RBC progenitor - Parvovirus B19 infection - infects and destroys RBC precursors

Immune-mediated injury of progenitors - 1) Aplastic anemia (lack of hematopoietic stem cells in bone marrow, pancytopenia (very very low RBCs, platelets, and WBCs)
2) Pure Red Cell Aplasia - Primary marrow disorder, only erythroid progenitors are suppressed

Increased RBC Destruction
1) Sickle Cell & Thalassemia
2) Acquired Cases I: Deficiency of Phosphatidyl-Inositol Linked Glycoprotein: -Paroxysmal nocturnal hemoglobinuria (PNH) -PNH results in increased suspectibility of RBCs to lysis by endogenous levels of complement.
3) Acquired Cases II: Antibody mediated: -Hemolytic disease of newborn -Transfusion reactions -Drug-induced -Auto-immune disorders
4) Acquired Cases III: Mechanical Trauma to RBCs: a) Microangiopathic Hemolytic Anemia --- -Thromotic thromocytopenic purpura (TTP), disseminated intra-vascular coagulation (DIC), hemolytic uremic syndrome (HUS). b) Cardiac trauma hemolysis (defective cardiac valves) c) Repetitive Physical Trauma (marathon running) d) Infections-Malaria e) Chemical injury - Lead poisoning

Microcytic Anemia: <80 cubic micrometers
USE MNEUMONIC FAST!!!!
-Fe deficiency anemia
-Anemia of chronic disease
-Sideroblastic anemia (iron rings around rbc due to lead poisoning)
-Thalassemia

Macrocytic Anemia: >100 cubic micrometers BIG FAT PIG (B12, Folate, Pernicious Anemia)
-Folate/vitamin B12 deficiency
-Alcoholism, drugs (methotrexate), myelodysplastic

Normocytic anemia: 80-100 cubic micrometers
-Anemia of chronic disease

Iron Deficiency Anemia
-Koilonychia (spoon-shaped nails)
-Cheilosis (Fissures at the angle of mouth)

Vitamin B12 deficiency - Subacute combined degeneration of spinal cord
-Tingling and numbness in hands & feet (parasthesia)
-Unsteady gait/difficulty in walking: Impaired senses

Hemolytic Anemia
-Jaundice
-Hepatosplendomegaly

CBC
-Hb
-Hct (the Hct should be x3 the Hb)
-RBC Count
-WBC count
-WBC/Platelet count to rule-out pancytopenia
-PBS evaluation
-Red cell indices

Reticulocyte Count
-To assess erythropoeietic activity

Other Tests
-ESR
-Serum bilirubin
-Hemoglobin electrophoresis
-Bone marrow examination (when cause of anemia is not evident)

Quantitative Hb Disoder - Thalassemia

Qualitative Hb Disorder - Sickle Cell Disease

Retic <3% Non-Hemolytic
-Acute Blood Loss <1 week
-Anemia of Chronic Disease
-Aplastic Anemia
-Renal disease
-Malignancy

Retic > or equal to 3% Hemolytic
Intrinsic RBC defect
-Membrane defect (Hereditary spherocytosis)
-Abnormal Hemoglobin (Sickle Cell Anemia)
-Enzyme Deficiency G6PD

Extrinsic RBC defect
-Immune hemolytic anemia
-Macro/micro angiopathic hemolytic anemia

Take Complete History
-Diet and Food Preparation
-Blood Loss
-Family History
-Recent Illness
-Past History of Anemia

Perform Physical Examination
-Pallor (skin, conjunctiva, mucous membrane)
-Murmur
-Liver/spleen/lymph nodes
-Jaundice
-Purpura (purple spots on skin due to bleeding of small blood vessels)
-Petechiae
-Ecchymosis - skin bruise due to coagulation defect

Serum iron - amount of circulating iron bount to transferrin

TIBC - indirect measure of circulating transferrin

Percent Saturation - [Serum Fe/TIBC] x 100: Normal Range: 25-50%

Serum Ferritin - Circulating fraction of storage iron