Alterations in Immunity (PATHO)

Altered immunity can result from

• Failure of host defense mechanisms: the impaired ability to mount an immune defense

  • Antigenic variation-Influenza (genetic mutations and new strains)

  • Latent-Tuberculosis (lays dormant in the body)

  • hypersensitivity

  • autoimmunity

  • alloimmunity

• Hypersensitivity

• inappropriate excessive immune responses

• Autoimmunity

• inappropriate response to “self”

• Alloimmunity

• reactions directed at tissue antigens from other individuals of the same species

Hypersensitivity (1 of 2)

• Altered immunologic response to an antigen that results in disease or damage to the host

• Immediate hypersensitivity reactions

  • Anaphylaxis

• Delayed hypersensitivity reactions

Hypersensitivity

• Characterized by the immune mechanism:

• Type I →immediate

• IgE mediated

• Type II→antibody mediated reaction

  • Tissue-specific reactions

• Type III

  • Immune complex mediated reaction

• Type IV

  • Cell mediated hypersensitivity reaction

Type I Hypersensitivity

• IgE mediated

• Against environmental antigens (allergens)

• IgE binds to Fc receptors on surface of
  mast cells—“sensitized”

• Histamine release from mast cell degranulation

• Antihistamines used in treatment (i.e. benadryl, epinephrine)

  • i.e. bee sting

Type I Hypersensitivity

• Manifestations:

• 
  

• GI allergy

  • Vomiting, diarrhea, abdominal pain

• Skin manifestations

  • Urticaria (hives)

• Mucosa allergens

  • Conjunctivitis, rhinitis, asthma

• Lung allergens

  • Asthma, bronchospasm, edema, thick secretions

Type I Hypersensitivity (3 of 3)

• Genetic predisposition—atopic

• Tests:

  • Food challenges

  • Skin tests

  • Laboratory tests

Type II Hypersensitivity (1 of 2)

• Tissue specific

  • Specific cell or tissue (tissue-specific antigens) is the target of an immune response

• Symptoms depend on tissue or organ involved

Type II Hypersensitivity (2 of 2)

• Five mechanisms that can affect cells:

• 
  

• Cell is destroyed by antibodies and complement

• Cell destruction through phagocytosis

• Tissues damaged by products of neutrophils

• Antibody-dependent cell-mediated cytotoxicity (ADCC)

• Target cell malfunction (e.g., Graves—targets thyroid)

Type III Hypersensitivity (1 of 2)

• Immune complex mediated reactions

• 
  

• Antigen-antibody complexes are formed in the circulation and are later deposited in vessel walls or extravascular tissues

• Antibodies bind to soluble antigens in blood or body fluids

• Large number of lysosomal enzymes released

• Not organ specific

Type III Hypersensitivity (2 of 2)

• Manifestations

• 
  

• Serum sickness

  • Caused by formation of immune complexes in blood and deposition in target tissues

  • e.g., Raynaud phenomenon

• Arthus reaction

  • Vasculitis caused by repeated local exposure

  • e.g., Celiac disease

Type IV Hypersensitivity

• Cell-mediated hypersensitivity reactions

• Does not involve antibody

• Cytotoxic T lymphocytes or lymphokine-producing Th1 and Th17 cells

  • Direct killing by Tc or recruitment of phagocytic cells by Th1 and Th17 cells

• Examples:

  • Graft rejection

  • Tuberculosis skin test

  • Allergic reactions from poison ivy or metals

Hypersensitivity Reactions

• Allergy

• 
  

• Deleterious effects of hypersensitivity to environmental (exogenous) antigens

Hypersensitivity Reactions

• Autoimmunity

• 
  

• Disturbance in the immunologic tolerance of
  Self-antigens

• Distinguish Self from nonself failure

• Graves; SLE

Hypersensitivity Reactions

• Alloimmunity

• 
  

• Immune reaction to tissues of another individual

• Graft rejection

Hypersensitivity Reactions

• Immune deficiency

• 
  

• Reaction insufficient to protect the host

Allergy (1 of 2)

• Allergens

• 
  

• Environmental antigens that cause atypical immunologic responses

• Pollens, molds and fungi, foods, animals, cigarette smoke, house dust

• Most common hypersensitivity and usually type I

Allergy (2 of 2)

• Anaphylaxis

• 
  

• Most rapid and severe immediate hypersensitivity reaction

• Occurs within minutes of reexposure to antigen

• Systemic or cutaneous

• Most severe reactions can lead to death

• Beestings, peanuts, shellfish, or eggs

• Desensitization

  • May reduce the severity of the allergic reaction but could also cause anaphylaxis

Autoimmunity

• Genetic, environmental, and random factors

• Tolerance

  • Self-antigens not normally seen by the immune system

  • Breakdown of tolerance causes body to recognize self-antigens as foreign

• Autoimmune diseases

  • Systemic lupus erythematosus

Systemic Lupus Erythematosus (1 of 3)

• Most common autoimmune disease

• Chronic multisystem inflammatory disease

• Autoantibodies against:

  • Nucleic acids

  • Histones

  • Ribonucleoproteins

  • Other nuclear materials

Systemic Lupus Erythematosus (2 of 3)

• Deposition of circulating immune complexes containing antibody against host DNA

• Symptoms the result of type II or III hypersensitivity reactions

• More common in females

Systemic Lupus Erythematosus (3 of 3)

• Clinical manifestations

• 
  

• Arthralgias or arthritis

• Vasculitis and rash

• Renal disease

• Hematologic changes

• Cardiovascular disease

• Manifestations may wax and wane and affect all body systems, difficult to diagnose

  • Laboratory diagnosis based on positive ANA screen

Alloimmunity

• Reaction against another individual’s tissues

  • Transfusion reactions

  • Transplant rejection

  • Fetus during pregnancy

• Alloantigens

  • Nonself antigens from members of the same species

  • Blood group antigens

  • Histocompatibility antigens

Transfusion Reactions

• ABO blood group

• 
  

• A and B carbohydrate antigens

• Blood types based on which are expressed

  • A

  • B

  • O (neither expressed)

  • AB (both expressed)

• Transfusion reaction occurs when person with one blood type receives another

  • Type O—universal donor

  • Type AB—universal recipient

Transfusion Reactions (3 of 3)

• Rh blood group

• 
  

• Antigens expressed only on RBCs

  • Rh-positive

  • Rh-negative

• Hemolytic disease of newborn

  • Rh-negative mothers with Rh-positive fetuses

Transplant Rejection

• MHCs (HLAs) are major target

• Classified according to time

  • Hyperacute

    • Immediate and rare

    • Preexisting antibody to the antigens of the graft

  • Acute

    • Days to months

    • Cell-mediated immune response

  • Chronic

    • Months or years

    • Weak cell-mediated reaction against minor HLA antigens

Immune Deficiencies

• Failure of immune mechanisms to function normally

  • Increased susceptibility to infections

• Primary (congenital) immunodeficiency

• Secondary (acquired) immunodeficiency

• Primary (congenital) immunodeficiency

• 
  

• Genetic anomaly

• Secondary (acquired) immunodeficiency

• 
  

• Caused by another illness

• More common

Immune Deficiencies

• Clinical presentation

• 
  

• Development of unusual or recurrent, severe infections

• T-cell deficiencies

  • Viral, fungal, yeast, and atypical microorganisms

• B-cell and phagocyte deficiencies

  • Microorganisms requiring opsonization

• Complement deficiencies

Primary Immune Deficiencies

• Most are the result of a single gene defect

• Generally not inherited

• May appear early or late in life

• Rare but increasing

Primary Immune Deficiencies

• Major groups:

• 
  

• Combined deficiencies

• Antibody deficient

• Phagocytic defects

• Innate immunity defects

• Complement defects

Combined Deficiencies

• Defects in development of both T and B lymphocytes

• Severe combined immunodeficiency (SCID)

  • Most severe of the disorders

  • Few detectible lymphocytes

  • Underdeveloped thymus

  • Absent or reduced IgM and IgA levels

diff Combined Deficiencies

• Bare lymphocyte deficiency

• Wiskott-Aldrich syndrome

• DiGeorge syndrome

• Bare lymphocyte deficiency

• 
  

• Adequate B and T cells but defective cooperation

• Inability to produce MHC class I and II

• Wiskott-Aldrich syndrome

• 
  

• Depressed IgM production with bleeding

• DiGeorge syndrome

• 
  

• Lack or partial lack of thymus and parathyroid gland

• Results in calcium deficiency

Predominantly Antibody Deficiencies

• Most common immune deficiency

• Defective B-cell development

  • May affect only one class of antibody or several

  • Hypogammaglobulinemia

  • Agammaglobulinemia

    • Bruton agammaglobulinemia

Phagocyte Defects

• Inadequate numbers or defects in function of phagocytes

• Chronic granulomatous disease (CGD)

  • Defect in myeloperoxidase-hydrogen peroxide system

  • Causes deficient production of products needed for phagocytic killing

  • Results in recurrent pneumonia; tumorlike granulomata in lungs, skin bones; and other infections

Defects in Innate Immunity

• Defect in capacity to produce immune response

• Chronic mucocutaneous candidiasis

  • Severe recurrent candida infections due to defective immune response to C.albicans

Complement Deficiencies

• C3 deficiency

• Mannose-binding lectin (MBL) deficiency

• C3 deficiency

• 
  

• Most severe defect due to central role in compliment cascade

• Results in recurrent life-threatening infections

• Mannose-binding lectin (MBL) deficiency

• 
  

• Primary defect of lectin pathway of complement activation

• Results in increased risk of infection with microorganisms that have polysaccharide capsules rich in mannose

Treatment for Primary Immune Deficiencies

• Treatment by replacing missing component

  • Intravenous immune globulin (IVIg)

  • Stem cell transplantation

  • Transfusion of erythrocytes

  • Bone marrow transplants

  • Mesenchymal stem cell injection

Secondary Immune Deficiencies

• Also referred to as acquired deficiencies

• Far more common than primary deficiencies

• Immune deficiency is often clinically irrelevant

  • Minor without increased susceptibility to infection

  • Substantially but only for a short time

• Severe deficiencies include

Secondary Immune Deficiencies

• 
  

• Malignancy

• Immunosuppressive treatments

• AIDS

Malignancies

• Complicated by immunosuppression

• Late-stage malignancies result in generalized deficiency of immune response

  • Increased risk of infections

• Many people with malignancies will die from infection rather than from the tumor

Immunosuppressive Treatments

• Many medications affect immune response

  • Most profound are those that intentionally suppress immune function to manage a disease

    • Corticosteroids

    • Chemotherapeutic agents

    • Irradiation

    • Antirejection drugs

Acquired Immunodeficiency Syndrome (AIDS)

• is the most advanced stage of infection caused by human immunodeficiency virus (HIV)

• HIV

  • Depletes the body’s Th cells

  • Creates generalized immune deficiency

Human Immunodeficiency Virus (HIV) Epidemiology

• 
  

• Blood-borne pathogen

• Heterosexual activity is most common route worldwide

• Women affected by HIV/AIDS more often

Human Immunodeficiency Virus (HIV)

• Structure

• 
  

• Retrovirus

• Genetic information is in the form of RNA

• RNA packaged inside a capsid incased in an envelope, along with

  • Reverse transcriptase

  • Integrase

  • Protease

• Envelope displays glycoproteins 120 and 41 (gp120 and gp41)

Human Immunodeficiency Virus (HIV)

• Life cycle

• 
  

• Attachment to target cell (Th lymphocyte) using gp120

• Viral capsid released into target cell cytoplasm

• Viral RNA inserted into target cell’s genetic material

• Formation and release of new virions

  • Have some host cell membrane

  • Less vulnerable to adaptive immune attack

Human Immunodeficiency Virus (HIV)

• Clinical manifestations

• 
  

• Serologically negative—no detectable antibody

• Serologically positive but asymptomatic—positive for antibody against HIV proteins

• Early stages of HIV—mild and nonspecific symptoms

  • Resemble influenza

  • Disappear after 1-6 weeks

• AIDS—more serious signs and symptoms

  • Atypical or opportunistic infections and cancers

  • Debilitating chronic disease

Human Immunodeficiency Virus (HIV)

diagnosis

• Diagnosis of AIDS

  • Decreased CD4+ T cell numbers (<200/mm³)

• Treatment and prevention

  • Antiretroviral therapy (ART)—combination of:

    • Chemokine receptor inhibitors

    • HIV fusion inhibitors

    • Reverse transcriptase inhibitors

    • HIV Integrase inhibitors

    • HIV Protease inhibitors

  • Death reduced significantly

  • Not curative

Pediatric AIDS

• Transmitted during pregnancy, at delivery, or through breast-feeding

  • ART in pregnant women has decreased risk of transmission

• Neurologic involvement common

• Infection progresses rapidly

  • Treatment must begin at time of diagnosis