Inadequate response = deficiency

Over/ Inappropriate response = hypersensitivity and autoimmunity

Immune deficiencies

Failure of immune mechanisms of self-defence

– Primary (congenital) immunodeficiency

– Secondary (acquired) immunodeficiency

o Due to another illness, drug, or environmental exposure

o More common

Primary Immune Deficiencies (with selected examples)

Most are the result of a single gene defect

Clinical presentation:

– Recurrent or persistent infections

– Developmental delay as a result of infection

Five groups:

1. B lymphocyte deficiencies

– Hypogammaglobulinemia or agammaglobulionemia

2. T lymphocyte deficiencies

– DiGeorge syndrome: Partial or complete absence of T cell immunity

o Congenital thymic aplasia or hypoplasia and diminished parathyroid gland development.

o It is caused by the lack or partial lack of the thymus, greatly resulting decreased T cell numbers and function.

o Leads to:

• Neural tube defect

• Abnormal development of facial features (low set ears, fish shaped mouth, wide eyes)

• Calcium deficiency

3. Combined T and B cell deficiencies

o Severe combined immunodeficiencies (SCID)

• Low T cells, very low IgM and IgA from underdeveloped thymus

o Wiskott-Aldrich syndrome (WAS)

• X linked recessive disorder.

• IgM antibodies are depressed.

• Very susceptible to bacterial infections and bleeding

o Ataxia-telangiectasia (AT)

4. Complement defects

o C3 deficiency

• Very severe. Lose C3 in the compliment cascade. Results in recurrent life-threatening infections with encapsulated bacteria

5. Phagocyte defects:

o Chediak-Higashi syndrome (lysosomal problem)

o Myeoloperoxidase deficiency (chronic granulomatous disease)

• Defect in myeloperoxidase–hydrogen peroxide system

• Causes deficient production of hydrogen peroxide needed in phagocytic killing

• Results in recurrent pneumonia; tumour-like granulomata in lungs, skin bones; and other infections

Secondary Immune deficiencies

Also known as, acquired deficiencies

More common than primary.

Causes:

Psychologic stress

Dietary insufficiencies

Malignancies

Liver disease

Physical trauma

Drugs

Viral:

– E.g. Acquired immunodeficiency syndrome AIDS

Evaluation of immunity

Complete blood count (CBC) with a differential

– Subpopulations of lymphocytes, granulocytes

Plasma levels of immunoglobulins (Ig)

– Subpopulations of immunoglobulins

Bone marrow examination

Serum complement levels (C3a, C5a)

Skin tests

Evaluation of body systems to identify causes

Hypersensitivity

Exaggerated immunologic response to an antigen that results in disease or host damage

Classification: (based on immune mechanism)

Type I

– Anaphylaxis (IgE mediated)

Type II

– Tissue specific reactions

Type III

– Immune complex mediated

Type IV

– Delayed cell mediated immunity

Type I

Immediate hypersensitivity reactions: occur within mins to a few hrs after exposure

Also known as allergy or anaphylaxis

Response to environmental antigens (allergens):

– Pollens, molds, fungi, foods, animals

IgE mediated

– IgE binds via its Fc receptor on surface of mast cells

– Degranulation and histamine release

Examples

Bronchial asthma

Bee sting

Clinical manifestations

Itching/urticaria (hives)

Conjunctivitis

Rhinitis

Hypotension

Bronchospasms

Dysrhythmias

GI cramps and malabsorption

Genetic predisposition

Most often

Tests

Food challenges

Skin tests

Lab tests

Desensitization

With caution

Type II

**Tissue specific

Immune response is directed to a specific cell/tissue/organ

Mechanism

Cells/tissues are destroyed by:

– Antibodies

– Complement system

– Phagocytosis

Result: cell/organ malfunctions

Examples

Grave’s disease (antibody against thyroid tissue)

Pernicious anemia

Some types of glomerulonephritis (Berger’s Disease)

Type III

**Immune complex mediated

Mechanism

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

Not organ specific (unlike type II)

Examples

– Serum sickness; Raynaud phenomenon Figure 26: Integrated processes of antigen recognition and cellular destruction

o A condition caused by the temperature-dependent position deposition of immune complexes in the capillary beds of the peripheral circulation. Certain immune complexes precipitate at temperatures below normal body temp, particularly in the nose, toes, tips of fingers and are called cryoglobulins. The precipitates block circulation and cause localized

pallor and numbness, followed by cyanosis.

– SLE (also considered autoimmune disease)

– Post-streptococcal glomerulonephritis

Type IV

**Cell-mediate

Do not involve antibody

Mediated by delayed cytotoxic T lymphocytes response

– Direct killing of cellular targets by Tc or recruitment of phagocytic cells by TH1 cells

Examples:

– Rheumatoid arthritis

– Graft rejection

– Tuberculosis

– Contact dermatitis

Autoimmunity

Breakdown of self-tolerance

– Body recognizes self-antigens as foreign and react to it

Genetic and environmental factors

Examples:

Antigenic mimicry:

– Rheumatic fever: reactions that occur within minutes to a few hours after exposure to an antigen

– Post infectious glomerulonephritis

Neoantigen:

– Newly acquired and expressed antigen

– Cancer immunity

Multisystem autoimmunity:

– Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematous (SLE)

Chronic multisystem inflammatory/autoimmune disease

Causes:

– Genetics

– Drug induced: hydralazine, procainamide and isoniazid

Pathophysiology

Development of autoantibodies against:

– Nucleic acids

– Erythrocytes

– Coagulation proteins

– Phospholipids

– Lymphocytes

– Platelets

Common features

– Facial rash (malar rash)

– Discoid rash

– Photosensitivity

– Oral or nasopharyngeal ulcers

– Non-erosive arthritis

– Serositis

– Renal manifestations

– Neurologic manifestations

– Hematologic manifestations

– Immunologic manifestations

– Positive antinuclear antibodies (ANA)

Criteria for Dx:

**Patient must have at least 4 out of the 11 symptoms = Positive SLE

Alloimmunity

Reacting to allo-antigens (external Ag from other species)

Includes:

– Transplant/graft rejection

– Transfusion reactions

Transplant rejection

Classified according to time

Hyper acute (rare)

– Immediate reaction (white-graft)

– Pre-existing antibody to the antigens within the graft (type II reaction to HLA antigens on the vascular endothelial cells in the grafted tissue)

Acute

– Rapid; weeks to months

– Cell-mediated immune response against major HLA antigens

– Infiltration of lymphocytes and macrophages (type IV reaction)

Chronic

– Months to years

– A weak cell-mediated response against minor HLA antigens

– Slow progressive organ failure

Graft-Versus-Host-Disease

T cells in the graft are mature and capable of cell-mediated destruction of tissues of the recipient

– Occurs in immunocompromised people

People with SCID are at high risk of GVHD

– GVHD targets skin, liver, mouth, eyes and GI tract

Risk can be diminished by removing mature T cells from the tissue used to treat individuals with immune deficiencies

Transfusion reactions

*ABO blood groups (mismatched transfusion):

– Reactions that occur within minutes to a few hours after exposure to an antigen

– Platelets alloimmunization (Platelets are covered in proteins and some people can develop ABs against platelets that are not their own.)

Rh incompatibility in pregnancy and “Hemolytic disease of newborn”

– Caused by IgG (anti-D alloantibodies) produced inside the body of Rh-negative mothers against erythrocytes of Rh-positive fetuses ( passed via placenta)

Review: Bacterial vs Viral infection

Bacterial:

Antibody mediated

Antigen presentation activates

– Th cells

– Tc cells

B cell activation and differentiation into plasma cell

Plasma cells secrete antibodies

Viral:

Antibody + cell mediated

Similar to above bacterial infection (for ab mediated portion)

For cell mediated

– Tc and NK cells activated by contact with virally infected cells

– Kill (lyse) virally infected cells

End of Module of Module