Pathophysiology Porth's ch. 15 Disorders of the Immune Response

Cell-mediated (T cell) immunodeficiencies

*- lack of T cells, have trouble fighting of viruses* - Result from defective expression of the T-cell receptor (TCR) complex, defective cytokine production, and defects in T-cell activation. - CD4+helper T cells - CD8+ cytotoxic T cells - Impair the ability of the immune system to protect against fungal, protozoan, viral, and intracellular bacterial infections (CD8+ cytotoxic T cells).

Humoral (B cell) immunodeficiences

*need B cells to fight off bacteria* B-cell dysfunction and decreased immunoglobulin (Ig) production Essential for normal defense against bacterial invasion and toxins that circulate in body fluids or enter the body through the mucosal surface of the respiratory or gastrointestinal tract. At increased risk for recurrent infections Not as important in defending against intracellular bacteria (mycobacteria), fungi, and protozoa. Body's response to viral infection is normal (unaffected)

Autoimmune diseases

- A heterogenous group of disorders that occur when the body's immune system fails to differentiate "self" from "nonself" - Loss of immunologic self-tolerance - Mounts an immunologic response against host tissues - Can affect almost any cell type, tissue, or organ system - Results in damage

Disorders of phagocytosis

- Defect causing disruption of: - Leukocyte adhesion (e.g., leukocyte adhesion deficiency or LAD) - Microbicidal production and activity (e.g., chronic granulomatous disease [CGD]), - Process of cellular degranulation (e.g., Chédiak-Higashi syndrome [CHS]) - Reduction in the absolute number of available cells - Susceptible to bacterial and fungal infections

Combined T and B-cell Immuno

- Defects in both the humoral and cell-mediated immune responses - End result is a disruption in the communication pathways between the cells of the humoral and cell-mediated immune systems and failure of the adaptive immune response. - Severe combined immunodeficiency

Criteria for determining an autoimmune disorder

- Evidence of an autoimmune reaction - Determination that the immunologic findings are not secondary to another condition - The lack of other identified causes for the disorder

Hypersensitivity disorders

- Excessive or inappropriate activation of the immune system Types: - Type I, IgE-mediated disorders - Type II, antibody-mediated disorders - Type III, complement-mediated immune disorders - Type IV, T-cell-mediated disorders activation of different parts of the immune system

Type III, Immune complex-mediated disorders

- Formation of antigen-antibody complexes in the bloodstream that are deposited in the vascular epithelium or extravascular tissues. - Activation of the complement pathway by the immune complex generates chemotactic and vasoactive mediators that cause tissue damage by: - alterations in blood flow - increased vascular permeability - destructive action of inflammatory cells

Mechanisms of autoimmune diseases

- Heredity - Susceptibility genes - Failure of self-tolerance - Breakdown of T-Cell anergy - Release of sequestered antigens - Molecular mimicry - Superantigens

Disorders of the complement system

- Leads to enhanced susceptibility to infectious diseases and to the development of a variety of autoimmune processes - Due to loss of activation of the complement system - Decreased or absent chemotaxis - Impaired opsonization - Decreased phagocytosis of invasive pathogens and bacteriolysis

Type II, Antibody-mediated disorders

- Mediated by IgG or IgM antibodies directed against target antigens on the surface of cells or other tissue components -->Result in complement-mediated phagocytosis and cellular injury - Complement-activated cell destruction - Antibody-mediated cell cytotoxicity - Complement- and antibody-mediated inflammation - Antibody-dependent modulation of normal cell surface receptors

Graft vs. host disease

- Onset varies - Donor T-cells in the graft proliferate and attack the recipient's tissue. - Most commonly seen in bone marrow transplants - Presentation: Diarrhea, rash and jaundice

phases of Type 1, immediate hypersensitivity phases

- Primary/Initial-phase - 5-30 mins of exposure: - Histamine release causes: - Vasodilation and vascular leakage - Smooth muscle contraction - Bronchial constriction - Secondary/Late-phase - 2-8 hours: - More intense infiltration of tissues with eosinophils and other acute and chronic inflammatory cells - Tissue destruction in the form of epithelial cell damage

Immunodeficiency

- abnormality in one or more parts of the immune system that results in an increased susceptibility to disease states normally eradicated by a properly functioning immune response

Immunodeficiency states

- humoral (b-cell) - cell-mediated (t-cell) - combines b-cell and t-cell - complement system - phagocytosis (neutrophils and macrophages)

Type 1, immediate hypersensitivity disorder

- this is what happens when you have an allergy - Develops rapidly upon exposure to an antigen (allergen) - IgE-mediated activation of mast cells and basophils with the subsequent release of chemical mediators of the inflammatory response - Anaphylactic reactions from food allergies - Atopic (local) reactions from Allergic rhinitis

Mechanisms postulated to explain the tolerant state

1) Self-tolerance 2) Central tolerance 3) Peripheral tolerance

Humoral immunodeficiency disorders

1) X-linked agammaglobulinemia (XLA) - An inherited, sex-linked, recessive disorder - Severe decrease in the production, maturation, and survival of mature B lymphocytes 2) Common variable immunodeficiency (CVID) - Low serum IgG levels, but some present with low IgA and/or low IgM as well, resulting in impaired antibody response to specific infections and vaccine challenge 3) Selective IgA deficiency (SIGAD) - Characterized reduction in levels of IgA - In the body, secretory IgA binds to and neutralizes intestinal pathogens and their toxic products, so IgA antibodies are normally not found in the bloodstream unless bacterial flora invasion has occurred 4) Immunoglobulin G Subclass deficiency - Deficiencies in one or more of the IgG subtypes, despite normal levels of overall serum IgG.

Type IV cell-mediated hypersensitivity disorders

A) Direct cell-mediated cytotoxicity (CD8+T cells) - Causes cell death and tissue injury in sensitized people - topically administered chemical antigens (contact dermatitis) - systemic antigen exposure - autoimmune process B) Delayed-type hypersensitivity - Presensitized CD4+ T cells release cytokines - damaging cells

Transplant rejection

A) Hyperacute Reaction - Occurs almost immediately - Type II hypersensitivity response B) Acute Rejection - Occurs within weeks to months - May occur months or years after immunosuppression has been terminated - Type IV hypersensitivity response C) Chronic Rejection - Occurs month to years later - Manifests with dense intimal fibrosis of blood vessels of the transplanted organ - The actual mechanism is unclear but may include release of cytokines that stimulate fibrosis. - Type III & IV hypersensitivity reaction

Adaptive Immune System

Ability to exhibit memory for invading organisms and toxic substances This response develops more slowly but with a great deal of specificity

Innate Immune System

Body's first line of defense against infection Employs rapid yet nonspecific cellular and chemical responses

Chronic Granulomatous Disease

CGD: most common forms of phagocyte dysfunction Increased susceptibility of both bacterial and viral infections as well as the development of lesions Cognitive defects but exact mechanism is unknown; bone marrow transplant is only known cure

Chediak Higashi Syndrome

CHS: Rare autosomal recessive disorder with immunodeficiency, susceptibility to infection, progressive neuro dysfunction Abnormally large granules are found in bone marrow and blood Manifest in early infancy and many do make it past teenage years

Laryngeal Edema

Can lead to complete airway obstruction and death without intervention Management: emergency management in cases of severe airway obstruction including intubation or tracheotomy

Self Tolerance

Capacity of immune system to differentiate self from nonself

Allergic Rhinitis

Common hypersensitive disorder of upper respiratory tract Nasal obstruction, sneezing, itchy and watery eyes Development of this is strictly airborne and are therefore deposited directly onto nasal mucosa

Anergy

Complete loss of lymphocyte response to an antigen and can result in a diminished or absent cellular/humoral immunologic response

T-Cell Mediated Deficiencies

Considered to be the most severe; those infected succumb to viral/fungal/opportunistic infections within the first few months of life Rarely survive beyond infancy; result from defect of T-cell activation Bone marrow transplant have been treatment of choice

Complement Activated Cell Destruction

Destruction of target cells in type 2 hypersensitive reactions This process activates macrophages to destroy target cells by phagocytosis

Hypersensitivity Reactions

Disorders caused by immune responses

Central Tolerance

Elimination of autoreactive lymphocytes during maturation in the central lymphoid tissues

DiGeorge Syndrome

Embryonic developmental defect associated with chromosome deletion; thought to occur before the 12th week Partial or complete failure of thymus, congenital defects of the head, neck, palate, and heart Autoimmunity is potential problem; treatment is dependent on symptoms

Hypersensitive Pneumonitis

Form of inflammatory lung disease that results from exaggerated immune response after exposure to a multitude of inhaled organic particles Labored breathing, dry cough, chills, fever, headache

Peripheral Tolerance

Functional suppression of autoreactive lymphocytes in peripheral tissue that have escaped destruction in the thymus

Cell Mediated Immunodeficiencies

Group of disorders that arise from defects in one or more components of the cell mediated immune response T lymphocytes work to protect against infection, control malignant cell proliferation, coordinate overall immune response

Epigenetics

Heritable changes occur as a result of changes in gene expression rather changes in DNA sequencing

Chronic Rejection

Involves immune mediated inflammatory injury to a graft that occurs over a prolonged period Most often due to the inability to maintain adequate immunosuppression to control residual antigraft T lymphocytes or antibodies

Histamine

Is the most recognized mediator of type 1 hypersensitivity reactions

Arthus Reaction

Localized immune complex reaction associated with discrete tissue necrosis usually in skin Caused by repeated exposure to an antigen; lesions are typically, red, raised, and inflamed Mechanism is not completely known

Secondary Cell-Mediated Immuno Disorders

More prevalent than primary and more associated with acute viral infections that impair cell immunity No known etiology but acquired later in life

Cellular Rejection

Most common form of acute allograft rejection is T cell mediated

Selective Immunoglobulin A Deficiency

Most common primary disorder; moderate to marked reduction in levels of serum and IgA Mechanism if IgA deficiency is unknown and no definitive treatment Manifestations are mild to absent

Humoral Immunodeficiency

Primarily associated with B-cell dysfunction and decreased Ig production There is an increased risk for recurrent infections

Autoreactivity

Process by which an organism acts against its own tissue

Transplantation

Process of taking cells, tissues, organs (graft), from one person and placing them into another person where they take over the normal function of the tissues replaced

Ataxia Telangiectasia

Rare, autosomal recessive disorder caused by gene mutation Involved in cellular response to breakage in the double strand helix of DNA Ataxia usually goes undiagnosed until child begins to walk; increased risk of cancer and radiation sensitivity Cognitive development ceases after about 10 years

Hereditary Angioneurotic Edema

Rare, life threatening complement disorder Inherited, autosomal dominant trait; uncontrolled release of substances that promote vascular permeability

Atopic Reactions

Reactions most commonly manifest as hives, allergic rhinitis, dermatitis, and bronchial asthma People prone to this often develop reactions to more than one environmental allergens with symptoms present at different times of the year

Systemic Immune Complex Disorders

Serum sickness results from formation of insoluble antigen-antibody immune complexes in presence of antigen excess Generalized tissue damage and edema; rash, fever Treatment involves removal of antigen and providing symptom relief

Wiskott-Aldrich Syndrome

Severe and complex X linked disorder; recurrent infection, eczema, increased risk for autoimmune disorders Life expectancy of about 15 years; key regulator of response to signals arising at cell membrane

Anaphylactic Reactions

Systemic life threatening Ig E hypersensitive reaction associated with widespread histamine into systemic circulation Can be graded on a scale of 1-4 Results from presence of even minute levels of allergen introduced into body by airway, skin, or blood

Primary Humoral Immunodeficiency Disorders

These are the result of impaired differentiation and maturation of lymphoid stem cells in the bone marrow Can interrupt the production of one or all of the Igs at any point along the cycle

Primary Immunodeficiency Disorders

These disorders are either congenital or inherited as sex linked autosomal dominant/recessive traits • Primary immunodeficiency disorders are inherited abnormalities of immune function that render a person susceptible to diseases normally prevented by an intact immune system. They can be classified as B cell-mediated, T cell-mediated, or combined immunodeficiencies, which affect all aspects of the humoral and cell-mediated immune response. • B cell-mediated immunodeficiency disorders affect antibody production and inhibit the ability of the immune system to defend against bacterial infections and toxins that circulate in body fluids (IgM and IgG) or enter the body through the mucosal surface of the respiratory or g astrointestinal tract (IgA). • T cell-mediated immunodeficiency disorders result from defective expression of the T-cell receptor (TCR) complex, defective cytokine production, and defects in T-cell activation. They impair the ability of the immune system to protect against fungal, protozoan, viral, and intracellular bacterial infections (CD8+ cytotoxic T cells).

Secondary Immunodeficiency

These disorders develop later in life as a result of other pathophysiologic states such as malnutrition, cancers, infection of cells of the immune system, immunosuppresive therapy (e.g. chemo, corticosteroids or transplant rejection medications)

Stem Cell Transplant

This is the treatment for most primary immuno deficiencies They can be harvested from bone marrow or peripheral blood but in less than 20% of cases can a match be found Can be taken from umbilical cord blood but it is unknown if it contains enough stem cells for effective use

Common Variable Immunodeficiency

This results in an impaired antibody response to specific infections and vaccines No one specific gene mutation has been found and affects male and females equally Can begin at any time of life and most commonly include bacterial/viral infections of respiratory tract

Allergenic Contact Dermatitis

Type 4 hypersensitive reaction Sensitization phase: haptens captured by dendritic cells and migrated to regional lymph nodes to stimulate T cell production Not uncommon for secondary infection to occur; affected area is swollen and warm, crusting appears

Transiet Hypogammaglobulinemia of Infancy

With this, there is a reduction in one or more serum Ig levels resulting in recurrent infection in infants An infants immune system is unable to properly synthesize enough Ig on its own

Immunologic tolerance

• Immunologic self-tolerance is the ability of the immune system to distinguish between self and nonself antigens. It is mediated through central and peripheral mechanisms that delete autoreac- tive immune cells or render them unresponsive to autoantigen. • The development of self-tolerance relies upon two coordinated processes: central tolerance, the elimination of autoreactive lymphocytes during maturation in the central lymphoid tissues, and peripheral tolerance, the functional suppression of autoreactive lymphocytes in peripheral tissues that have escaped destruction in the thymus.

Allergic and hypersensitivity disorders

• Type I hypersensitivity reactions are dependent upon IgE-mediated activation of mast cells and basophils and the subsequent release of chemical mediators of the inflammatory response. • Type II (antibody-mediated) hypersensitivity or cytotoxic hypersensitivity reactions are mediated by IgG or IgM antibodies directed against target antigens on specific host cell surfaces or tissues and result in complement-mediated phagocytosis and cellular injury. • Type III (immune complex) hypersensitivity is caused by the formation of antigen-antibody i mmune complexes in the bloodstream, which are subsequently deposited in vascular epithelium or extravascular tissues and which activate the complement system and induce a massive inflammatory response. • Type IV (cell-mediated) hypersensitivity involves tissue damage in which cell-mediated immune responses with sensitized T lymphocytes cause cell and tissue injury. Although all are T cell mediated, the pathophysiologic mechanisms and sensitized T-cell populations involved differ.