Immunologic Disorders

This antibody is:

• Most abundant antibody in the body

• Important for secondary immune response

• Can cross the placenta

IgG

This antibody is:

• Present in physiological secretion of the body

• In monomer form in serum

• Dimer form in glandular secretions

• Responsible for activation of alternate pathway

IgA

Antibody that is:

• Important to primary immune response

• Have maximum molecular weight/size

• Pentamer

• AKA millionaire’s antibody

• Functions as a B cell receptor

• IgM and IgG (IgM > IgG) are responsible for activation of a classical pathway

IgM

Antibody that is:

• Increased in allergic reactions

• AKA homocytotropic antibody or reaginic antibody

IgE

Antibody that functions as a B cell receptor

IgD

• Normal defense becomes self-destructive; self antigens become foreign.

• Reactions are characterized by B-cell hyperactivity and hyper-gammaglobulinemia.

• May be related to T-cell abnormality.

Autoimmune reactions

Causes of autoimmune reaction

Can be combination of genetic, hormonal, and environmental influences

Exaggerated or inappropriate immune response occurring after second exposure to antigen. Leads to inflammation and destruction of tissue

Hypersensitivity

Allergen activates T-cells, including B-cell production of IgE which binds to receptors on Fc surface of mast cells (IgE mediated)

• repeated exposure is needed for this to occur

• sensitization to allergen occurs when enough IgE is produced

Next contact with allergen, antigen binds to IgE, crosslinks with Fc receptors, mast cells degranulate, and release various mediators resulting in hypotension wheezing, swelling, urticaria, and rhinorrhea

Type I hypersensitivity 

In type I hypersensitivity, sensitization to allergen occurs when

When enough IgE is produced after repeated exposure to antigen

Examples of type II hypersensitivity

• Graves disease

• Autoimmune hemolytic anemia

• Blood transfusion reactions

• Autoimmune thrombocytopenic purpura

Hypersensitivity reaction where antibodies are directed towards cell; surface antigens play a role in target cell destruction

• Antigen-antibody complex activates complement leading to membrane attack complex that leads to cell lysis

• Phagocytic cells with receptors for IgE (Fc region) and complement fragments phagocytize tagged targets

• Natural killer cells and cytotoxic T cells damage tissue by releasing toxic substances

• Antibody binding leads to immobilization or malfunction of target cell 

Type II hypersensitivity 

Term refers to deleterious effects of hypersensitivity to exogenous (environmental) antigen (e.g. cat dander, pollen)

Allergy

Term refers to endogenous antigen, or a disturbance in the immunologic tolerance of sel-antigens (e.g. systemic lupus erythematosus (SLE), rheumatoid arthritis(

Autoimmunity

AKA isoimmunity. Term refers to immune reaction to donor tissues of another individual; same species

Alloimmunity

Hypersensitivity onset

• May be immediate or delayed

• Immediate (minutes to hours)

• Delayed (most severe several hours after re-exposure)

Hypersensitivity that is tissue specific; AKA IgG-mediated cytotoxic hypersensitivity

Type II hypersensitivity 

Antigen-antibody complex in type II hypersensitivity

Activates complement leading to membrane attack complex that leads to cell lysis

Phagocytic cells in type II hypersensitivity

Phagocytic cells with receptors for IgE (Fc region) and complement fragments phagocytize tagged targets

Natural killer cells and cytotoxic T cells in type II hypersensitivity

Damage tissue by releasing toxic substances

Antibody binding in type II hypersensitivity

Binding leads to immobilization or malfunction of target cell 

Circulating antigen-antibody complexes accumulate and deposit in tissues

• Complement activated, leading to local inflammation

• Platelets release vasoactive amines, causing increased vascular permeability leading to accumulation of immune complexes in vessel walls

• Complement fragments attract neutrophils; neutrophils attempt to phagocytose immune complexes and release lysosomal enzymes that cause tissue damage

Type III hypersensitivity 

Hypersensitivity that is immune complex-mediated

Type III hypersensitivity 

Hypersensitivity that is cell-mediated

Type IV hypersensitivity 

Ab directed against cell surface Ags mediates cell destruction via complement activation or ADCC (Antibody-Dependent Cellular Cytotoxicity) 

Type II hypersensitivity

Ag-Ab complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils

Type III hypersensitivity

Sensitized TH1 cells release cytokines that activate macrophages or Tc cells which mediate direct cellular damage

Type IV hypersensitivity

Examples of type III hypersensitivity

Serum sickness; glomerulonephritis; SLE (Systemic Lupus Erythematosus), rheumatoid arthritis, celiac disease

How does type III hypersensitivity damage the body?

Circulating antigen-antibody complexes accumulate and deposit in tissues

• Complement activated, leading to local inflammation

• Platelets release vasoactive amines, causing increased vascular permeability leading to accumulation of immune complexes in vessel walls

• Complement fragments attract neutrophils; neutrophils attempt to phagocytose immune complexes and release lysosomal enzymes that cause tissue damage

Examples of type IV hypersensitivity

• Poison ivy

• Autoimmune thyroiditis (Hashimoto’s disease)

• Tuberculin skin test

• Acute graft rejection

• Contact allergic reactions

• Some autoimmune diseases

Antigen-presenting cells (APCs) bring antigen to T cells

→

Sensitized T cells release lymphokines, which stimulate macrophages

→ 

Lysozymes are released, and surrounding tissue is damaged

Type IV hypersensitivity 

Acute potentially life-threatening type I (immediate) hypersensitivity reaction marked by sudden onset of rapidly progressive urticaria (vascular swelling in skin accompanied by itching) and respiratory distress

Anaphylaxis

Anaphylaxis onset

Occurs within minutes but can occur up to 1 hour after re-exposure

Anaphylaxis steps

1) Response to antigen

2) Release of chemical mediators

3) Intensified response

4) Respiratory distress

5) Deterioration

6) Failure of compensatory mechanisms

Causes of anaphylaxis

Ingestion of or systemic exposure to sensitizing drugs or other substances such as

• Serums

• Penicillin or other antibiotics, sulfonamides, local anesthetics

• Diagnostic chemicals (sulfobromophthalein sodium, sodium dihydrofolate, radiographic contrast media)

• Food proteins

• Sulfite-containing food additives

• Insect venom

Clinical manifestations of anaphylaxis

• Activation of IgE and subsequent release of chemical mediators → feeling of impending doom or fright

• Histamine release → sweating, sneezing, SOB, nasal pruritus, urticaria, angioedema, nasal mucosal edema, profuse watery rhinorrhea, itching, nasal congestion

• Increased vascular permeability, subsequent decrease in PVR and leakage of plasma fluids → hypotension, shock, cardiac arrythmias

• Bronchiole smooth muscle contraction and increased mucus production → hoarseness, stridor, wheezing, and accessory muscle use

• Smooth muscle contraction of intestines and bladder → severe stomach cramps, ND, urinary urgency/incontinence 

Activation of IgE and subsequent release of chemical mediators in anaphylaxis leads to

Feeling of impending doom or fright

Mass histamine release in anaphylaxis leads to

Sweating, sneezing, SOB, nasal pruritus, urticaria, angioedema, nasal mucosal edema, profuse watery rhinorrhea, itching, nasal congestion

Increased vascular permeability, subsequent decrease in PVR, and leakage of plasma fluids in anaphylaxis leads to

Hypotension, shock, cardiac arrythmias

Bronchiole smooth muscle contraction and increased mucus production in anaphylaxis leads to

Hoarseness, stridor, wheezing, and accessory muscle use

Smooth muscle contraction of intestines and bladder in anaphylaxis leads to

Severe stomach cramps, ND, urinary urgency/incontinence

Management of anaphylaxis

• If patient is conscious/normotensive → Immediate admin of epi 1:1,000 aqueous solution IM or SubQ 

• If reaction is severe → epi IV

• Repeat doses every 5-20 mins if necessary

• Tracheostomy or ETT intubation and mechanical ventilation

• O2 therapy

• Longer-acting epi, corticosteroids, diphenhydramine (Benadryl)

• Albuterol mini-nebulizer treatment

• Histamine-2-blocker

• Volume expanders

• IV vasopressors (epi/norepi

• CPR

If patient experiencing anaphylaxis is conscious/normotensive →

Immediate admin of epi 1:1,000 aqueous solution IM or SubQ 

If anaphylactic reaction is severe →

Administer epi IV

Condition that inhibits body’s ability to defend against infection or injury Can result from impaired function of any or all WBCs, and/or deficient complement or coagulant proteins.

• Can be congenital OR acquired

Immunodeficiency

May involve one

• Type of T or B cell or all T cells (DiGeorge syndrome)

Congenital immunodeficiency

Congenital immunodeficiency that affects all the T cells

DiGeorge Syndrome or Hypoplastic thymus

Congenital immunodeficiency that affects all the B cells

Bruton’s agammaglobulinemia

How is B cell deficiency treated?

Missing immunoglobulin may be administered through injection

Congenital immunodeficiency where dysfunctional pluripotential stem cells leads to deficiency of T, B, and all other WBCs.

Severe combined immunodeficiency syndrome (SCIDS)

Treatment for SCIDS

Gene therapy

Congenital immunodefiency characterized by lack of certain HLA antigens that present to T cells, leads to

Failure of T cell immune function (usually causes death in early childhood) 

Acquired immunodeficiency may arise in response to

• Chronic stress

• Renal failure

• Infection

• Malnutrition

• Pregnancy

• Diabetes

• Liver cirrhosis

CRIMPDL (causes of acquired immunodeficiency)

Response to:

C – Chronic stress/corticosteroids/chemotherapy

R – Renal failure/radiation therapy

I – Infection

M – Malnutrition

P – Pregnancy

D – DM

L – Liver cirrhosis

Drugs/procedures that suppress the immune system/cause acquired immunodeficiency

• Corticosteroids

• Chemotherapy

• Radiation therapy

• Anesthesia

• Surgery

The elderly are often immunodeficient. True or false?

True

Why are geriatric/elderly immunodeficient?

Due to

• Progressive decrease in function of the thymus

• Poor blood flow due to atherosclerosis

• Diabetes

• Poor nutrition

Consequences of immunodeficiency 

• Frequent, severe, and unusual infections that patient cannot cope with

• T cell deficient patients develop viral and yeast infections (especially HIV) 

• B cell deficient patients susceptible to infections by bacteria may require opsonization 

T cell patients are susceptible to

Viral and yeast infections (e.g. HIV)

Chronic, systemic inflammatory disease that primarily attacks peripheral joints and surrounding muscles, tendons, ligaments, and blood vessels. Is also an autoimmune disease

Rheumatoid arthritis

Disease is characterized by partial remissions and unpredictable exacerbations

Rheumatoid arthritis

Synovitis develops from congestion and edema of the synovial membrane and joint capsule

→

Infiltration of WBCs sustains local inflammatory response

→

Immune cell enzymes degrade/damage bone and cartilage

This happens in what stage of rheumatoid arthritis?

1st stage of rheumatoid arthritis

Pannus (thickened layers of granulation tissue) covers and invades cartilage leading to the destruction of the joint capsule and bone. This happens in what stage of rheumatoid arthritis?

2nd stage of rheumatoid arthritis 

Fibrous ankylosis (stiffness) occludes the joint space

→

Bone atrophy and misalignment causes visible deformities and disrupts articulations

→

Muscle atrophy occurs, leading to subluxations (term for partial dislocation)

This happens in what stage of rheumatoid arthritis?

3rd stage of rheumatoid arthritis

Fibrous tissue calcifies, resulting in bony ankylosis and total immobility. This happens in what stage of rheumatoid arthritis?

4th stage of rheumatoid arthritis

Abnormal stiffening and immobility of a joint due to fusion of the bones. Occurs in rheumatoid arthritis

Ankylosis

Pharmacological management of rheumatoid arthritis

• Salicylates (aspirin) & NSAIDs (Motrin, Indocin, Nalfon) → anti-inflammatory

• Anti-malarials (Plaquenil, sulfasalazine, gold salts, and penicillamine) → reduce chronic inflammation

• Corticosteroids (e.g. prednisone) → immunosuppressive effect

• Azathioprine, cyclosporine, methotrexate → in early disease immunosuppression

Surgical management of rheumatoid arthritis

• Synovectomy → remove proliferating tissue

• Osteotomy → realign joint

• Joint reconstruction → treat or correct deformities

• Tendon transfer → relieve contracture/deformities

• Arthrodesis (joint fusion) → stability and pain relief

Slowly progressing, diffuse autoimmune connective tissue disease that mostly affects women; is characterized by inflammatory, degenerative, and fibrotic changes in skin, blood vessels, synovial membranes, skeletal muscles, and internal organs

• May be localized (skin and musculoskeletal)

• May be generalized (includes internal organs)

Scleroderma

Scleroderma mostly affects women or men?

Women

Localized scleroderma

Affects skin and musculoskeletal system

Generalized scleroderma

Affects internal organs

Scleroderma onset location

First in fingers, then in upper arms, then in shoulders, then neck and face

Disease has 

Initial inflammation, followed by fibrotic and degenerative changes in skin, blood vessels, synovial membranes, skeletal muscles, and internal organs (esophagus, intestinal tract, thyroid, heart, lungs, and kidneys)

• Disease continues to progress and affect other areas

Clinical manifestations of scleroderma

• Skin begins to atrophy

• Edema with infiltrate containing Cd+4 T cells (TH) surround blood vessels

• Collagen fibers become edematous, weak and less elastic, followed by degeneration

• Dermis becomes tightly bound to underlying structures

• Dermal appendages atrophy, osteoporosis destroys distal phalanges

Chronic inflammatory autoimmune disorder of connective tissue that affects multiple systems that causes widespread inflammation. Is characterized by recurring remissions and exacerbations.

Systemic lupus erythematosus (SLE)

Clinical manifestations of SLE

• Lungs: tachypnea, cough, pleural inflammation/effusion

• CV: Raynaud’s, pericarditis, vascular inflammation

• Skin: Photosensitivity, erythematous rash to areas exposed to light, butterfly rash over cheeks

• Kidneys: lupus nephritis, proteinuria, hematuria

• Systemic: weight loss, fatigue, fever (infection), hematologic and neurologic disorders

How does SLE affect the lungs?

Tachypnea, cough, pleural inflammation/effusion

How does SLE affect the cardiovascular system?

Raynaud’s, pericarditis, vascular inflammation

How does SLE affect the integumentary system?

Photosensitivity, erythematous rash to areas exposed to light, butterfly rash over cheeks

How does SLE affect the kidneys?

Lupus nephritis, proteinuria, hematuria

What are the systemic effects of SLE?

Weight loss, fatigue, fever (infection), hematologic and neurologic disorders

How does SLE affect the immune system?

• Immune dysregulation in the form of autoimmunity

• B cell hyperactivity of immune responses due to antigen-antibody complexes

• Production of auto-antibodies against blood cells: RBCs, neutrophils, platelets, lymphocytes, and almost any organ/tissue in body

• Widespread degeneration of connective tissue

• Possible CV, renal, or neurologic complications from severe bacterial infection

Causes of SLE

Idiopathic. Could be linked to:

• Environmental factors

• Infections

• Abx/certain drugs

• UV light

• Extreme stress

• Hormones

Universal donor

O

AB

Universal recipient

Blood type incompatible with B and AB; has anti-B antibody and A antigen

Blood type A

Blood type incompatible with A and AB; has anti-A antibody and B antigen

Blood type B

Blood type is is compatible with all blood types. no antibodies, and A & B antigen

Blood type AB

Has no antigen, and anti-A and anti-B antibodies; incompatible with types A, B, AB

Blood type O

Rh system

• Is primarily expressed on erythrocytes

• Rh-positive: expressed D antigen on RhD protein

• Rh-negative: does not express the D antigen

Rh-positive

Expresses D antigen on RhD protein

Rh-negative

Does not express the D antigen

What happens if Rh-negative individuals are exposed to Rh-positive erythrocytes?

Rh-negative start making anti-D antibodies (someone with Rh-negative can only receive negative blood; Rh-positive can receive both)

Newborn hemolytic disease (transfusion reaction)

Rh-negative mother gives birth to Rh-positive infant

Are the result of a single gene defect; classified in 5 groups:

• B lymphocytes deficiencies

• T lymphocyte deficiencies 

• Combined T & B cell deficiencies

• Complement defects

• Phagocyte defects

• Hypo/agammaglobulinemia 

Primary immune deficiencies 

• Are acquired

  • Caused by another illness

  • Are more common that primary

Secondary immune deficiencies 

• Immunocompromised individuals are at risk for this disease

• T cells in graft are mature and capable of cell-mediated destruction of tissue within recipient

• Not a problem if patient is immunocompetent

Graft vs. Host disease (GVHD)

Treatment for immunodeficiencies

• Gamma-globulin therapy

• Transplantation or transfusion

• Treatment with soluble immune mediators

• Gene therapy

• Alloimmune reaction

• Matching human leukocyte antigens (HLA)-DR locus → most critical for graft acceptance 

• Transplant rejection is classified by time

Graft rejection (host vs graft)