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Chapter 3

Disorders of the Immune System

The Nature of DiseasePathology for the Health Professions

Thomas H. McConnell

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Brief Review of Adaptive Immunity

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Overview of Immune Disorders

• Immune disorders fall into 3 major categories:– Hypersensitivity disorders

• Caused by an allergen (antigen causing an allergic resp.)

• Allergic rhinitis, anaphylaxis

– Autoimmune disorders• Immune system attacks self

• RA, SLE

– Immunodeficiency disorders• Absent or depressed immune response (primary;

acquired)

• DiGeorge syndrome, AIDS

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Hypersensitivity

• Exaggerated immune response• Environmental or internal antigens• Associated more closely with certain HLA genotypes

• Four types– Type I: immediate hypersensitivity (allergic; anaphylactic) [B cell]

– Type II: cytotoxic hypersensitivity [B cell]

– Type III: immune-complex hypersensitivity [B cell]

– Type IV: cellular hypersensitivity (delayed) [T cell]

• Mnemonics: ACID and AnGST

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Type I (Immediate) Hypersensitivity

Important points:

- Immediate (after initial sensitization) - Antigen is extrinsic (foreign) - Local or systemic - B cell (ab) mediated - IgE - Mast cells (histamine; other mediators) - Examples - Allergic rhinitis (seasonal = hay fever) - Anaphylaxis (local or systemic) - One form of latex allergy (to the latex

itself)

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Type II (Cytotoxic) Hypersensitivity

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Important points:

- Usually immediate (> sensitization) - Ag is extrinsic or intrinsic - May be initiated by a hapten - Local or systemic - B cell (ab) mediated - IgG or IgM - Ab attach to cell surface - Cell injury from: - Complement - NK Cell, phagocytes (ADCC) - Altered cell function - Examples - Txfusion Rexn - Grave’s Disease - Myasthenia Gravis - Autoimmune hemolytic anemia

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Type III (Immune Complex) Hypersensitivity

Important points:

- Usually immediate (> sensitization) - Antigen not fixed in tissue - Local or systemic hypersensitivity - B cell (ab) mediated - IgG or IgM - Damage from ag-ab complexes - Examples - SLE - Serum sickness - Farmer’s Lung - One form of latex allergy (to the

latex itself) Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Type IV (Delayed Type) Hypersensitivity

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Important points:

- Delay (28-48 hrs) - T cell mediated - Damage from TCTL attack - Examples - TB - Transplant rejection - Contact dermatitis (poison ivy) - Latex allergy (to chemicals used) - Granulomatous inflammation - Rheumatoid arthritis - Multiple sclerosis - Type I Diabetes Mellitus

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Allergic Disorders and Atopy• Allergy: Exaggerated, but otherwise normal immune

response to foreign antigen (regardless of the type of hypersensitivity response)

• Allergen: an inciting foreign substance• Atopy: allergy due to type I hypersensitivity

– Common

– Usually affect: nose, skin, and airways (-> atopic triad: rhinitis, dermatitis, asthma

– Strong familial (genetic) tendency

– Pathophysiology is from IgE-sensitized mast cells

– Food allergies (infants: milk, soy, eggs, peanuts, wheat; adults: usually nuts and seafood)

– Anaphylaxis

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Autoimmune Disorders• Self antigens become targets of the immune system

• Affects ~ 2% of US population; autoimmune ab common, especially in elderly

• Clinical manifestations are extremely varied

• Genetic susceptibility, e.g., HLA-B27 and rheumatoid disease

• Some hypothesized causes:– Imperfect T and B cell programming

– Inaccessible self-antigens that become exposed for the first time to the immune system

– Molecular mimicry

• antigenic determinants of an infectious agent or foreign protein may be shared with self antigens

• Ab produced by B cells cross-react with self antigens

– Infection and inflammation

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Selected Autoimmune Disease

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Systemic Lupus Erythematosus (SLE)• Chronic inflammatory, rheumatic, autoimmune disease

characterized by remissions and exacerbations

• Etiology unknown (UV?, genetic?, hormonal?)

• Leukemia and renal failure usually major cause of death

• Classifications– Systemic lupus - involvement of 1 or more of these systems:

Musculoskeletal, Lungs, Kidneys, CNS, CVS, hematological

– Discoid lupus - limited to skin involvement

– Drug-induced lupus – procainamide, hydralazine, isoniazid

• Pathophysiology– Anti-DNA/RNA (antinuclear) autoantibodies produced by hyperactive B cells

• Detection test is very sensitive, but not very specific

– Other autoantibodies against RBCs, platelets, lymphocytes

– Autoantibodies+antigens -> Type III immune complex disease

– IC cause vasculitis with inflammation and necrosis

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Systemic Lupus Erythematosus (SLE)

Malar (“butterfly” ) phtotsensitive rash

Figures from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Scleroderma (Systemic Sclerosis)• Pathophysiology

– Etiology unknown (genetic?, immune?, environmental?)

– Microvascular damage, inflammation, *fibrosis of interstitium

– Many organs can be affected, especially the dermis

• Types of scleroderma– Systemic sclerosis

– CREST syndrome• Calcinosis

• Raynaud’s phenomenon

• Esophageal dysfunction

• Sclerodactyly

• Telangiectasis

– Localized or limited; skin on fingers, hands, and face (better prognosis)

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Amyloidosis• Amyloid – mixture of insoluble, mis-folded,

crystalline proteins; some may be Ig fragments• Amyloidosis – Any dysfunction resulting from

deposition of amyloid protein• Examples:

– Light chain amyloidosis (in B cell malignancies)

– Reactive systemic (with chronic inflammatory disease)– Hereditary (primary) amyloidosis – caused by several gene

defects, e.g., hereditary Mediterranean fever

– Amyloidosis of aging• Islets of Langerhans (Type II diabetes)

• Endocrine tumors (some)

• Brains of patients with Alzheimer’s DiseaseFigure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Tissue Transplantation• Successful transplantation is highly dependent upon

having as close a match as possible between tissue antigens (MHC/HLA and ABO) of donor and recipient

• Except for an autograft, every transplant has a possibility of rejection; immunosuppressive therapy

• Types of rejection (an immune reaction)– Hyperacute; minutes or hours due to preformed ab

– Acute• most common and treatable

• T and B cells involved

• Rejection mediated by cellular immune response

• Signs of inflammation with fever, redness, swelling, tenderness

– Chronic; 4 months to years causes chronic vasculitis compromising blood flow to transplant

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Graft versus Host Disease (GvHD)• Frequent and potentially fatal complication of bone

marrow transplant– Immunocompetent cells of the donor recognize the

recipient’s tissues as foreign

– Cell-mediated response

– Host is typically immunocompromised and unable to fight grafted cells’ attack

– Other areas affected: skin and GI tract (lots of epithelial cells), liver

• Acute GvHD: dermatitis, diarrhea, jaundice• Chronic GvHD: dermal sclerosis, Sjogren’s syndrome,

immunodeficiency

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Transfusion Reactions• Minimized by careful testing prior to transfusion:

– Major crossmatch: donor RBCs with recipient plasma

– Minor crossmatch: donor plasma with recipient RBCs

• Two major types of transfusion reactions:– Major

• Incompatible blood types

• Recipient’s pre-existing ab hemolyzes of donor’s RBCs

• Severe hemolysis, thrombosis, DIC, renal failure, death

– Minor• Any rexn NOT potentially life-threatening

• Fever, chills, back pain, hives, rash

• Erythroblastosis Fetalis (hemolytic disease of the newborn) - mother generates anti-Rh antibodies against fetal RBCs

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Immune Deficiencies• Failure of immune mechanisms of self-defense• Primary (congenital) immunodeficiency

– Genetic anomaly

• Secondary (acquired) immunodeficiency– Caused by another illness

• Clinical presentation– Development of unusual or recurrent, severe infections

(usually opportunistic infections)

– T cell deficiencies• Viral, fungal, yeast, and atypical microorganisms

– B cell and phagocyte deficiencies• Microorganisms requiring opsonization (bacteria, some viruses)

– Complement deficiencies

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Primary Immunodeficiencies• Affect the development of T and B cells

• Isolated IgA deficiency (B cells)– Most common primary immunodeficiency

– Recurrent infections of mucous membranes

• X-linked agammaglobulinemia -Bruton Disease (B cells) – X-linked recessive defect of B cell development

– Recurrent infections by about 6 months of age• Bronchitis, pneumonia, sinusitis, pharyngitis, otitis, GI infections

• Intestinal parasites and certain viral infections

• Thymic hypoplasia (DiGeorge syndrome) (T cells)– Deficient T cell function due to failure of thymus to develop

– Area around thymus often affected: neck, face, ears, heart, aorta

– Viral, fungal, protozoan infections

• Severe combined immunodeficiency - SCID (B and T cells)– Lymphoid tissues and thymus underdeveloped; lack of functional immunity

– Wide variety of infections before 6 months of age; total isolation required

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Acquired Immunodeficiency Syndrome (AIDS)• By far most common cause of acquired (secondary)

immunodeficiency

• Follows infection with Human Immunodeficiency Virus (HIV-1 (US), HIV-2 (W. Africa))– Humans are the only reservoir;

no animal reservoir

– Virus attaches to CD4 antigen of TH (and related macrophages) but must also use several other receptors (chemokine) to infect, i.e, CD4 is necessary but not sufficient for infection

– Reverse Transcriptase (RT) allows the RNA genome to be ‘reverse’ transcribed into DNA, and the abnormal DNA is inserted into host genome

– Corrupted cellular DNA produces new HIV RNA and virus particles

– Virus particles exit dying cell to infect other cells

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Additional HIV/AIDS Terminology & Facts• Modes of transmission for HIV virus

• Contact with infected blood or blood products during transfusion or transplantation

• Contact with infected body fluids, e.g., semen, vaginal fluids

• Across the placenta from infected mother to fetus

• Although HIV is also found in saliva, urine, tears, and feces there’s no evidence of transmission through these fluids

• Viral load - number of circulating HIV particles/ml (should be zero)

• Opportunistic infection – Any infection resulting from a deficient immune system, i.e., patient is immunocompromised or immunosuppressed

• Peripheral blood CD4+ TH cell counts are a reliable indicator about the progress of the disease; the lower the counts the more advanced the disease and the poorer the prognosis

• Current treatment regimen (Highly Active Antiretroviral Therapy, HAART) has dramatically extended the life expectancy of HIV-infected patients

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Phases of HIV Infection and AIDS

Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

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Classification of HIV Infection/AIDS is complex

* Category B symptomatic conditions are defined as symptomatic conditions occurring in an HIV-infected adolescent or adult that meet atleast one of the following criteria:

– They are attributed to HIV infection or indicate a defect in cell-mediated immunity.

– They are considered to have a clinical course or management that is complicated by HIV infection.

# Category C AIDS Indicator conditions include:

- Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or chronic weakness and documented fever for ≥1 month

- A number of associated conditions, e.g., Bacterial pneumonia, recurrent (two or more episodes in 12 months); Candidiasis of the bronchi, trachea, or lungs; Candidiasis, esophageal; Cervical carcinoma, invasive, confirmed by biopsy; Coccidioidomycosis, disseminated or extrapulmonary; Encephalopathy, HIV-related; ,Kaposi sarcoma; Mycobacterium tuberculosis, pulmonary or extrapulmonary; Pneumocystis jiroveci (formerly carinii) pneumonia (PCP); Toxoplasmosis of brain

Table from: http://aidsetc.org/guide/hiv-classification-cdc-and-who-staging-systems

Immunocompetent

Immunosuppressed

AIDS