General Pathology: Final Exam

Protection against infections

Immunity

Collection of cells and molecules that protect us against pathogenic microbes in our environment

Immune System

1) Leukocyte mediated damage w/o abnormal immune response

2) Immune-mediated damage due to hypersensitivity (allergic disease) or autoimmune mechanisms

What are the mechanisms of tissue injury in inflammation?

Immediate response

Is the innate immune response immediate/delayed?

Epithelial barriers (skin, GI, respiratory), macrophages (monocytes), neutrophils, innate lymphoid cells, and complement system (circulating plasma proteins), NK cells (innate lymphoid cells)

Major players of the innate immune system

Always present

Is innate immunity always/transiently present?

Prescence of antigens/microbes -> cause generation/expansion of mechanisms for neutralizing and eliminating threat

What does the adaptive immune system respond to?

Lymphocytes and their products (T/B cells)

Major players of the adaptive immune system

Capture protein antigens (and process) and display the peptides for recognition by T-lymphocytes

How do Dendritic cells work?

They are sentinels! They detect danger and initiate immune responses as a result; they themselves do not participate in the destruction of microbes

What is the purpose of dendritic cells?

Destroy severely distressed or abnormal cells -> infected cells/tumor cells

What is the function of natural killer cells?

Express CD16 -> receptor the heavy chain tails of IgG: if cell coated with IgG due to infection, this allows the NK cell to bind (antibody dependent cell cytotoxicity)

What receptor do NK cells express, and why?

Cytotoxicity regulated delicately by a balance of of inhibitory/activating signals; They themselves can also release cytokines to aid the process of eliminating/neutralizing a pathogen to propagate the process

NK cytotoxicity regulation

1) Humoral

2) Cellular

What are the two adaptive immune responses?

Mediated by antibodies secreted by B lymphocytes

What is humoral immunity mediated by?

Kills extracellular microbes

What is the purpose of extracellular immunity?

Mediated by T lymphocytes

What is cellular immunity mediated by/

Protection against intracellular microbes, direct killing of infected cells, and activation of phagocytes to kill ingested microbes

Function of cellular immunity

Morphologically identical (but functionally and phenotypically distinct)

How distinct are lymphocytic populations morphologically?

Single antigen; but due to somatic rearrangement, the entire population of lymphocytes can recognize a multitude of different antigens (lots of diversity!)

How many antigens can a T or B cell recognize? How can the body recognize so many different antigens

Bone marrow

Where are B-cells produced mainly?

Thymus

Where are T-cells produced mainly?

Produce antibodies that are capable of neutralizing the microbe, phagocytize the microbe, and activate the complement system

Function of the B lymphocyte

Secrete cytokines that promote inflammation, activate macrophages, and activate (proliferation and differentiation) of T and B lymphocytes

Function of Helper T cell

Kill infected cells

Function of cytotoxic T-cell

Down-regulate immune response

Function of regulatory T-cell

T-cells

What makes up the majority of lymphocytes in the peripheral blood?

Spleen and lymph nodes

Where are the major population of T-cells found?

Recognize fragments of antigens bound in combination with MHC molecules displayed on surfaces of cells

How do T-cells recognize antigens?

TCR-CD3

What receptors do all T-cells have?

CD8+

What unique receptors do cytotoxic T-cells have?

MHC I

What MHC receptor do cytotoxic T cells recognize?

CD4+

What unique receptors do helper T cells have?

MHC II

What MHC receptor do helper T-cells recognize

Display peptide fragments of protein antigens for recognition by antigen specific T-cells

Function of MHC receptors in general

Display peptides derived from cytoplasmic proteins -window to whats going on with the cell (normal vs/ tumor/viral infected)

Function of MHC I recepors

Present on virtually all cells of body

Where are MHC I receptors present?

Display peptides from proteins synthesized outside of cells

Function of MHC II receptors

Expressed constitiutively on professional antigen presenting cells (dendritic cell, macrophages, B cells)

Where are MHC II receptors present?

Lymph nodes, spleen, tonsils, MALT

Where are the major populations of B cells found?

Stimulation from helper T-cells

What do B-cells need to proliferate?

Altered reactivity to a specific antigen that results in pathologic reactions upon exposure to a sensitized host (one that has already been exposed to a specific antigen) to that of a specific antigen

Hypersensitivity reaction

Host sensitized to antigen

What is the exposure phase?

When the hypersensitivity response occurs (2nd time exposed and on)

What is the effector phase?

Immediate hypersensitvity (typical anaphylaxis)

What is type I hypersensitivity?

Antibody-mediated cytotoxic hypersensitivity

What is type II hypersensitivity?

Immune-complex mediated hypersensitivity

What is type III hypersensitivity?

Cell-mediated/delayed-type hypersensitivity

What is type IV hypersensitivity?

Types I, II, II

Which hypersensitivity diseases are mediated by antibodies?

Type IV

Which hypersensitivity diseases are mediated by T cells?

Antigen-specific IgE

What are type I hypersensitivity reactions induced by?

Activates mast cells to release preformed granules that are responsible for the new reaction as well as cytokines that are responsible for the late phase reaction

What does the effector phase in type I hypersensitivity reactions?

Vasodilation, edema, smooth muscle contraction, mucus production, recruitment of inflammatory cells (especially eosinophils)

Pathologic lesions of I hypersensitivity reactions

Antigen specific IgG or IgM

What are type II hypersensitivity reactions induced by?

Antibodies can be directed against antigens attached on the surfaces of cells and tissues resulting in destruction/damage of the cells or tissues

What is the result of the effector phase of the type II hypersensitivity reactions?

1) Opsoinization and phagocytosis

2) Complement and/or Fc receptor-mediated inflammation and damage

3)Anti-body-mediated cellular dysfunction

3 mechanisms of causing disease in type II hypersensitivity reactions

Both antigen-specific antibodies and complemented activated by antibodies act as opsonins resulting in phagocytosis

How does opsonization and phagocytosis work in type II hypersensitivity reactions?

IMHA, ITP, neonatal isoerythrolysis

Examples of diseases caused by opsonization and phagocytosis in type II hypersensitivity reactions

Antibody-dependent cell cytotoxicity -> Antibodies attract inflammatory cells (phagocytic/cytoxic cells) via binding of Fc receptors; Complement by-products (C3a and C5a) are chemotactic for neutrophils and other inflammatory cells, complement activation also results in formation of membrane-attack-complexes that result in cell lysis -> more inflammation

How does complement and/or Fc receptor-mediated inflammation and damage work in type II hypersensitivity reactions?

Pemphigus complex (when body attacks proteins of upper-skin resulting in blistering), ANCA-mediated vasculitis

Examples of diseases caused by type II hypersensitivity reactions

Antibody binding to cell surface receptors can either act as agonists or antagonists

How does antibody-mediated cellular dysfunction work in type II hypersensitivity reactions?

Myasthenia gravis

Examples of diseases caused by antibody-mediated cellular dysfunction in type II hypersensitivity reactions

Ab-Ag complexes can be deposited in places they shouldn't which result in damage/thrombosis

How can type III hypersensitivity reactions cause damage?

Ag-Ab complexes form locally at site of antigen exposure/administration (think testing for tuberculosis)

How do localized reactions of type III hypersensitivity reactions work?

Allergic pneumonitis, "blue eye" (canine adenovirus 1)

Examples of localized type III hypersensitivity reactions

Ab-Ag complexes are present in circulation and deposited in various sites throughout the body

How do generalized reaction of type III hypersensitivity reactions work?

Blood vessels, synovial membranes, glomerular capillaries, choroid plexus

Common sites of Ab-ag deposition in type III hypersensitivity reactions

FIP, systemic lupus erythematosus, serum sickness disease, rheumatoid arthritis

Examples of generalized type III hypersensitivity reactions

-Direct cytotoxic actions of CD8+ T cells

-Release of cytokines from CD4+ T cells, which activate inflammatory cells (primarily macrophages)

How do type IV hypersensitivity reactions cause disease?

Chronic, granulomatous inflammation

What are the characteristic results of type IV hypersensitivity reactions?

Antigens that are difficult to clear (Ex: Mycobacterium spp. -> Tuberculosis, Johne's disease; Fungal infections, Foreign body responses, and allograft rejections)

What induces type IV hypersensitivity reactions?

Autoimmune disease

A specific immune response to self-antigens -> loss of immunologic tolerance to self-antigens

Occurs during development in the thymus and bone marrow -> Lymphocytes exposed to a variety of self-antigens (sequestered/priveleged self-antigens not shown like lens proteins/sperm), those that react with self-antigens are deleted

What is central tolerance and how does it work?

B cells can undergo receptor editing, whereby an altered receptor is created

What can B cells undergo in central tolerance?

A way to delete self--reactive lymphocytes that have escaped bone marrow and thymus

What is peripheral tolerance

1) Anergy

2) Suppression by T-regulatory cells

3) Activation induced cell death

3 mechanisms of peripheral tolerance

Functional inactivation of lymphocytes that encounter antigen -> those that do not encounter a secondary signal fro APCs become anergic

How does anergy work/what is it?

T-regulatory cells that encounter their specific antigens will produce immunosuppressive cytokines

What is suppression by regulatory T-cells and how does it work?

Persistent stimulation of T cells by APCs eventually results in cell death -> main mechanism of down-regulation of immune response normally

How does activation induced cell death work?

Epitope spreading (immune response starts w/ one antigen and then shifts to another), exposure of hidden antigens (due to tissue damage like in lens and testicle which are highly inflammatory), molecular mimicry (antibodies to infectious antigens may react with self-peptides if close enough in structure)

How can infections and tissue injury result in auto-immune disorders?

Autoimmune syndrome characterized by a vast array of autoantibodies in which injury is caused mainly by deposition of immune complexes

What is systemic lupus erythmatosus?

Anti-nuclear antibodies are a characteristic feature but are present in other diseases

Characteristic feature of systemic lupus erythematosus

Immunodeficiency syndrome

Failure of immune system to protect host from infectious organisms or the development of cancer

Secondary/acquired immunodeficiency (drugs, infectious, malnutrition aging, irradiation)

Which kind of immunodeficient syndromes are more common?

Mutations in leukocytes ability to adhere to endothelium of vessels -> prevents leukocyte migration to area of infection -> lack of ability to fight infections-> primary immunodeficiency of innate immunity

What is leukocyte adhesion defects?

Arabians and jack-russel terriers cannot produce B/T cells due to mutation in development; Basset Hound and Welsh Corgis have no T cells and increased numbers of B cells due to mutation in development -> Primary immune deficiency (adaptive)

What is Severe combined immunodeficiency deficiency?

Lack T-cells and are unable to develop effective antibody responses due to genetic defect that result in atrichia and thymic aplasia -> primary immunodeficiency (adaptive)

What are athymic nude mice?

Agensis

Complete absence of an organ and primordium

Need microscopic evidence

What do you need to make a definitive Ddx of agensis?

Aplasia

Absence of an organ due to failure of growth of the associated primordium

Need microscopic evidence, especially when trying to determine if agenesis vs aplasia -> aplasia should have cells of the primoridum, where as agenesis should not

What do you need to make a definitive Ddx of aplasia?

Aplasia

What is more common, agenesis or aplasia?

Epitheliogenesis imperfecta (aplasia cutis) -> absence of epithelium from the surface (can happen in neonates of most species)

Example of Aplasia

Atresia

Absence of an opening, usually of a hollow organ

Atresia X -> Ex: Atresia Ani (Atresia of anus)

Naming of atresia in distal GI tract

X Atresia -> Ex: Esophageal Atresia

Naming of atresia in proximal GI tract

Hypoplasia

Failure of tissue to develop to normal size

Primary or secondary to in untero viral infections

What can hypoplasia be caused by?

Feline panleukopenia virus (parvo virus in cats), bovine viral diarrhea virus (pestivirus in ruminants and swine) and other fetal viral infections

What in utero viral infections can cause hypoplasia?

Agenesis, aplasia, hypoplasia

Order hypoplasia, agenesis, and aplasia from least common to most common