BL.2.7: Type 1 Immunopathologies, Hematopathology

Question 1

Please define: atopic, immediate hypersensitivity, allergy/allergen, anaphylaxis, asthma, hives, wheal-and-flare reaction

Answer 1

Atopic means “out of place,” and so was originally one of the words doctors coin to mean “we don’t know.” Also means prone to develop any of the range of allergic syndromes.immediate hypersensitivity: introduction of an allergen to a person with a few highly activate IgE clones will cause mast/basophil cells to release histamine → inflammation, vessel dilation, itching.allergy: a hypersensitive rxn to common, often intrinsically harmless substances.allergen: the substance that causes an allergic response.anaphylaxis: an exaggerated, life threatening hypersensitivity rxn to a previously encountered antigen. Mediated by IgE/G.asthma: reversible bronchoconstrictive disease with progressive inflammation leading to fibrosishive = wheel and flare rxn = rash of round, red welts on the skin that itch intensely, sometimes with dangerous swelling, caused by an allergic reaction

Question 2

State the approximate incidence of atopic diseases in the general population, and in individuals with allergic parents.

Answer 2

Estimates as high as 20% of all people have been published; â–º15% seem more likely to experience allergic symptoms at some time in their lives.There is a strong multifactorial genetic component.Risk of developing allergy climbs to 35% if a newborn has one allergic parent, and to 65% with two such parents.

Question 3

Describe the mechanism of IgE-mediated hypersensitivity in terms of: IgE attachment to basophils or mast cells; reaction with allergens; mediator release; effects of mediators on target tissues and cells.

Answer 3

The basic mechanism is straightforward: IgE binds strongly to FcεR1 receptors on the surface of mast cells. When 2 adjacent IgE molecules so bound are cross-linked by allergen, the mast cell is signaled to release the contents of its characteristic granules, including histamine, which causes local or systemic vasodilation and increased permeability, and gut and bronchial smooth muscle contraction.

Question 4

Discuss the features that the various atopic diseases have in common which justify lumping them together.

Answer 4

The atopic disease all involve an atypical immune response to environmental antigens and an increased reactivity or hypersensitivity of the end-organs to inflammatory mediators and irritants.While the locations of the allergic response may different in the various diseases - they are mediated by the same players: histamine, IgE, mast cells.

Question 5

Discuss the reasons for using glucocorticoids in asthma treatment.

Answer 5

The late-phase reactants and Th2 cells present in the lung are pro-inflammatory, and untreated chronic inflammation inevitably leads to fibrosis, which is irreversible.Inhaled glucocorticoids are added early to the asthma treatment regimen; they are scarcely absorbed and can be used, with monitoring, in growing children without the serious side effects associated with systemic steroid treatment.They inhibit the production of arachidonic acid from phospholipids and thus block both PG and LT synthesis. They also induce apoptosis in eosinophils.

Question 6

Discuss intradermal skin tests with reference to procedure, safety and specificity.

Answer 6

The intradermal allergy test is more accurate because a defined dose (usually 50-100 μL) of extract is delivered into (not under) the skin. Observe for 15 or 20 minutes, record results as diameter of the central raised wheal/ diameter of the flare (e.g., 5/15 mm).Buffer injection is necessary to control for skin hyperreactivity. A positive control, using a histamine-releaser like codeine, may also be used.If a person has very severe allergy even this test can be dangerous and is best done by specialists who are skilled in treating adverse reactions. Observe all patients for 20-30 minutes after skin testing.A positive skin test does not necessarily mean that your symptoms are due to that allergen; your level of sensitivity may be subclinical even with a positive test, or your symptoms may come from something else that cross-reacts with the test extract.

Question 7

Discuss specific immunotherapy of allergic disease, considering duration of effect, risk of anaphylaxis, percent of patients obtaining significant relief.

Answer 7

Avoidance: Compliance toughAntihistamines: effective early and if symptoms are acuteEpinephrine: powerful vessel constrictor for emergencies. Those with significant allergies (airway risk) carry with them.Cromolyn Sodium: inhalant, makes histamine release from granules difficultTheophylline: inhalant, phosphodiesterase inhibitor, relaxes bronchial smooth muscleGlucocorticoids: treatment best when kept locally, multiple side effects systemically. Inhibit PG and LT synthesis.Leukotriene Inhibitors: zero info.IgE binding: for severe/life threatening allergies. Monoclonal Ab against IgE. So little in blood that all IgE can be mopped up by omalizumab.Allergy Shots: Mechanism unclear. dilute solution of allergen extracts injected. Build up immunity. 75% with seasonal rhinitis say season is easier.

Question 8

Describe the immediate allergic reaction and the late-phase reaction in terms of:Time course of the reaction,Mediators involved

Answer 8

Immediate: very quickly - within minutes; mediators = IgE, allergen, histamine, heparin, enzymes, TNFLate Phase: 4-10 hours after allergen introduced. Mediators = prostaglandins, leukotrienes attract eosinophils (together called ECF-A), and cytokines released by the mast cell.

Question 9

Discuss the roles of IgG, IgE, M2 macrophages, and eosinophils in helminth immunity.

Answer 9

IgG coat the helminth, activate complement which fails. As worm sheds it crosslinks IgE on mast cell which causes histamine granules to be released causing violent peristalsis.Late phase response stimulates PGs and LTs→ attracting eosinophils which have Fc receptors for IgG. Aha! Eosinophils engage worm and release Major Basic Protine (MBP) which is toxic to helminths.Th2 meanwhile is out in the body attracting Eos and Macrophages. Friendly chemokines (IL4/5/13) alternatively convert them to M2 Macrophages which wall of the invader. Magical.

Question 10

Outline the Hygiene or Old Friends Hypothesis.

Answer 10

It says that certain harmless microorganisms—notably non-tuberculosis Mycobacteria, lactobacilli, and helminth worms—have been in humans so long that we rely on their presence to instruct our immune systems not to overreact against commensals or low-grade pathogens.Thus, if you have adequate exposure to these old friends, you develop a balance between Th1 and Th2, driven, most importantly, by the right number of Treg.But if you were old-friendless at a critical developmental stage, perhaps between 0 and 2 years, you may have too few Treg and be too ready to make a strong Th1 or Th2 response to some organism that really isn’t much of a threat (gut flora) or is no threat at all (pollen), especially if you have a genetic predisposition to do so.

Question 11

Define leukemia and lymphoma.

Answer 11

Leukemia: a broad term given to a group of malignant diseases characterized by diffuse replacement of bone marrow with proliferating leukocyte precursors, abnormal numbers and forms of immature white cells in circulation, and infiltration of lymph nodes, spleen, and liver.Lymphoma: a type of neoplasm of lymphoid tissue that originates in the reticuloendothelial and lymphatic systems.

Question 12

Describe what types of cells might be found in leukemia and what types of cells might be found in lymphoma.

Answer 12

Leukemic cells may be either myeloid cells or lymphoid cells (Myeloid cells: ganulocytes, monocytes, megakaryocytes, erythrocytes C. Lymphoid cells: B-cells, T-cells, NK-cells)Non-Hodgkin lymphomas are lymphomas of B, T, and NK-cells. Hodgkin lymphoma are Reed-Sternberg cells.

Question 13

Explain what the difference is between leukemia and lymphoma when the same neoplastic cell is involved in each.

Answer 13

Leukemia: primary source of clones is in bone marrow.Lymphoma: primary source of clones is in lymph node.

Question 14

Describe the chief characteristic of the cells in an acute leukemia and the cells in a chronic leukemia.

Answer 14

Acute leukemia: Phenotypically - The neoplastic cells are immature, usually blasts. Clinically - The course of the disease is rapidly fatal without treatmentChronic leukemia: Phenotypically - The neoplastic cells are maturing/mature. Clinically - The course of the disease is relatively indolent, with a potential for long-term survival without treatment

Question 15

Discuss the features used by the WHO to define hematolymphoid diseases.

Answer 15

A central goal of the WHO 3rd and 4th Editions was to define “real” diseases that can be reproducibly diagnosed by pathologists using currently available techniques.definition of real diseases is based on morphology, immunophenotype, genetic features, and clinical features.The current state of knowledge varies from one disease to the next, so the importance of any one of these four features is variably important in defining a particular “real” disease entity.

Question 16

Discuss acute myeloid leukemia (AML) in terms of sites of involvement, how many blasts are required for diagnosis, and where the blasts may be found.

Answer 16

A monoclonal proliferation of immature, usually blastic myeloid cells, primarily in the bone marrow that variably manifests in the peripheral blood (rarely leukemia may occur outside the bone marrow).For a diagnosis of AML to be made there must be 20% or more myeloid blasts in the peripheral blood or bone marrow.Blasts are most often neutrophilic myeloblasts or monoblasts, although other types of myeloid blasts may be involved (rarely) as well as more “mature” myeloid cells (see below).

Question 17

Discuss who is most likely to get AML.

Answer 17

AML tends to be a disease of older people with a median age of 65 years.AML is more common in men than womanAML is less common in children – 15 to 20% of acute leukemia cases in children are AML.AML in children is most likely to occur in the first 3 to 4 years of life

Question 18

Describe CD34, CD45, and myeloperoxidase in terms of what cells express them and how they are used in the diagnosis of AML.

Answer 18

CD34 is a stem/progenitor cell antigen. It is expressed by both AML, and ALL (but not always).CD45 is also called leukocyte common antigen (LCA). It is positive in AML and ALL.The myeloperoxidase enzyme may be immunologically detected in the cytoplasm of leukemic cells.

Question 19

Describe the 5 groups of AML according to the WHO classification system.

Answer 19

AML with recurrent cytogenetic changesAML with myelodysplasia-related changesTherapy-related myeloid neoplasmsAcute myeloid leukemia, not otherwise specified (NOS)Myeloid sarcoma

Question 20

Describe the acute leukemia with t(15;17)(q22;q12) in terms of its leukemic cell, its complications, and its treatment.

Answer 20

t(15;17)(p22;q23) AML is associated with abnormal promyelocytes – thus it is usually called acute promyelocytic leukemia (APL). These promyelocytes have bilobed “dumbbell”- shaped nuclei. The cytoplasm of these abnormal promyelocytes is packed with large red-purple granules. Some cells contain bundles of Auer rods. There is also a microgranular variant of in which the granules are sub-microscopic in size.Factors produced by the abnormal promyelocytes in APL may cause disseminated intravascular coagulation (DIC) resulting in hemorrhage in a significant number of patients presenting with the disease – 20%. Less often patients may present with thrombosis. Treatment with ATRA rapidly improves the hemorrhage. Unfortunately a portion of patients who receive all-trans retinoic acid (ATRA) will go on to develop thrombosis.

Question 21

Describe how the AML group AML

Answer 21

NOS” includes all myeloid cell types.”

Question 22

Describe the 4 myelodysplastic syndrome (MDS) groups as listed in your notes.

Answer 22

Subtypes with dysplasia of only one cell line and less than 5% blasts in the bone marrow: Refractory cytopenias with unilineage dysplasia.Myelodysplasia with isolated del(5q). This subtype is characterized by macrocytic anemia and thrombocytosis. In the bone marrow there are hypolobated megakaryocytes. There are less than 5% blasts in the bone marrow. This is generally a disease of elderly women; the prognosis is good.Refractory cytopenia with multilineage dysplasia (RCMD). In this subtype there is dysplasia of 2 or three cell lines (multilineage dysplasia means that there must be dysplasia of 2 or more myeloid cell lines). There are less than 5% blasts in the bone marrow. In the peripheral blood there are one or two cytopenias.Refractory anemia with excess blasts (RAEB): In these subtypes there is dysplasia in 1 to 3 cell lines. In the peripheral blood there are 1 to 3 cytopenias. RAEB 1 or 2. 1 = 5-9% blasts in marrow, < 5% in peripheral blood. 2 = 10-19% blasts in marrow, 5-19% in peripheral blood.

Question 23

Discuss what is meant by dysplasia.

Answer 23

Any abnormal development of tissues or organs. An alteration in cell growth resulting in cells that differ in size, shape, and appearance, often as a result of chronic irritation.

Question 24

Describe the features of MDS. Include in your discussion the bone marrow, the peripheral blood, and cells.

Answer 24

These syndromes are clonal myeloid disorders characterized by dysplasia of one or more of the myeloid cell lines (erythroid, megakaryocytic, granulocytic), ineffective hematopoiesis due to increased apoptosis resulting in varying degrees of marrow failure manifested by anemia, neutropenia and/or thrombocytopenia.There may be worsening marrow failure and there is an increased risk of developing AML.The signs and symptoms of MDS are similar to those of AML and relate to marrow failure. Physical signs and symptoms of MDS may include fatigue, pallor, ecchymoses, petechiae, abnormal bleeding, and infection.

Question 25

Discuss potential outcomes in a patient with MDS.

Answer 25

Prognosis and prognostic factors. A scoring system has been devised that predicts a patient’s median survival and risk of developing acute leukemia. In Table 4 Median Survival is the median number of years in a particular category that a patient will survive; 25% AML Evolution is the median number of years it takes for 25% of patients in a particular group to develop acute leukemia (these are not to be memorized).These tables indicate that an increasing number of blasts, a complex karyotype, and increasing cytopenias (anemia, neutropenia, thrombocytopenia) in MDS is associated with a greater chance of developing acute leukemia and a reduced median survival.

Question 26

Discuss how many blasts can be present in the peripheral blood and bone marrow in MDS.

Answer 26

MDS Subtype: Refractory anemia with excess blasts (RAEB). In these subtypes there is dysplasia in 1 to 3 cell lines. In the peripheral blood there are 1 to 3 cytopenias.RAEB-1: There are 5 to 9% blasts in the bone marrow. There are less than 5% blasts in the peripheral blood.RAEB-2: There are 10 to 19% blasts in the bone marrow. There are 5 to 19% blasts in the peripheral blood. Auer rods may be present.

Question 27

Discuss the importance of cytogenetics in the diagnosis of MDS and predicting prognosis in MDS.

Answer 27

A scoring system has been devised that predicts a patient’s median survival and risk of developing acute leukemia. Cytogenetics place a critical role in this algorithm. See table below.