Module 4

Immunodeficiency

Disorder caused by reduced/absent immune system function

Primary Immunodeficiency

Congenital
Genetic defect
Abnormal immune system maturation
Low survival rate

Primary: B-Cell Deficiencies

Dysfunctional/decrease B lymphocytes
Increase infection susceptibility
Encapsuled bacteria (gram)

B-Cell Deficiencies: Symptoms

First symptoms: 7-9 months
Decrease maternal antibodies
Cannot synthesize normal antibodies

B-Cell Deficiencies: X-Linked Agammaglobulinemia

X-linked recessive disorder
Mostly males affected
No mature B cells
Low IgG and immunoglobulins
Increase bacterial susceptibility
No change in viral and fungal susceptibility
Normal cell-mediated response

Primary: T-Cell Deficiences

Dysfunctional/decrease T lymphocytes
Increase susceptibility to viruses, protozoans, fungi
Frequent infections (3-4 months)
Ex: pneumonia, candidiasis

T-Cell Deficiencies: DiGeorge Syndrome

Small segment deletion in chromosome 22
Absent/underdeveloped thymus
No mature T-cells
Heart, face, palate abnormalities
Learning disabilities

Primary: Complement Deficiencies

Deficient protein regulating pathways (9 components)
Frequent bacterial infections
Cannot clear immune complexes

Complement Deficiencies: C3

Most severe
Central role in complement activities

Complement Deficiencies: Hereditary Angioedema

No C1 regulator
Face, lips, larynx, GI swelling
Suffocation
Acute abdominal pain

Primary: Phagocytic Deficiencies

Innate immunity
Deficient phagocytosis stages
Frequent bacterial and fungal infections
Deep abscesses

Phagocytic Deficiencies: Chronic Granulomatous Disease

No bacteria-killing chemicals in phagocytes
Non-malignant granuloma formation
Small immune cell aggregations in nodes
Separate foreign material

Primary: Combined T- and B-Cell Deficiencies

Dysfunctional/decrease lymphocytes
Affect all adaptive responses
Little/no infection resistance
Mild pathogens become life threatening
Fatal infections

Combined T- and B-Cell Deficiencies: Bubble Boy

Severe Combined Inherited Immunodeficiency

Secondary Immunodeficiency

Acquired
Environmental factors compromise immune system
Chemotherapy, immunosuppressive meds, chronic infection, cancer
Ex: AIDS

AIDS

Acquired immunodeficiency syndrome
Final stage of HIV infection

HIV

Cell-associated virus
Cause AIDS
No treatment
Lytic and lysogenic viral cycles

HIV: Transmission

Location dependent (sex, vertical from mother to child, injections)
Viral replication in transmission fluid

Enveloped Virus

Unstable
Quickly die outside host
Ex: HIV

Unenveloped Virus

Stable
Remain active outside host for long time

Lytic Viral Cycle

Cause host cell lysis

Lysogenic Viral Cycle

Incorporate viral genome into host

AIDS Stage 0: Primary Infection

Effective immune response at beginning
Ineffective response after
HIV compromise immune system

AIDS Stage 1: Acute Infection

Innate response activation
HIV infect and decrease CD4+ T-cells
Small helper T-cell increase from antibody formation
Increase blood HIV levels
Increase transmission risk

AIDS Stage 2: Chronic Infection and Clinical Latency

HIV multiplies at steady rate
No symptoms
Transmission possible
Anti-HIV antibodies develop
HIV evade immune response with high antigen mutation
8-10 years

AIDS Stage 3: AIDS

Deplete CD4+ T-cells constantly fighting HIV infection
Helper T-cell < 200cells/mm3
Increase viral load
Weaken immune system
Increase opportunistic infection susceptibility
No treatment = 3 year survival

Antiretroviral Therapy

Prevent HIV replication
No progression to AIDS
Combo different antiretroviral drugs
Prevent resistance by mutations

Highly Active Antiretroviral Therapy (HAART)

Maintain immune system function
Prevent opportunistic infections

Immunodeficiency Screening

Identify disease presence in pre-symptomatic or unrecognized symptomatic individuals
Early intervention/management
Reduce suffering/mortality

Screening: Complete Blood Counts (CDC)

Measure cell type presence in blood
Compare to healthy reference range
Identify blood defects causing immunodeficiency

Screening: Quantitative Serum Immunoglobulin

Measure IgG, IgA, IgM levels in blood serum
Compare to control

Serum: Hypogammaglobulinemia

Low antibody levels
Humoral immunodeficiency
Further testing identifies source (CDC, urine protein electrophoresis)

Autoimmunity

Overactive immune system
Attack healthy cells and tissues
Immune reaction to self

Autoimmune Disease

Disease from autoimmunity
5-7% of pop
Mostly in females (78%)

Autoimmune Disease Development

Genetics
Bacterial/viral infection
Chemical exposure

Antiantibodies

Antibodies against self antigen

Organ-Specific Autoimmune Diseases

Immune response against antigen for 1 organ/gland
Thyroid gland, stomach, adrenal glands, pancreas

Organ-Specific: Graves Disease

Hyperthyroidism: Overactive thyroid gland
Abnormal TSH

Thyroid-Stimulating Hormone (TSH)

Produced by pituitary gland
Negative feedback
Regulate thyroid hormone production
Bind thyroid cell receptors
Control metabolism

Abnormal TSH

Autoantibodies to TSH receptor
TSH overproduction
Metabolic dysfunction

Graves Disease Causes

Genetics
Environment

Graves Disease: Thyroid Overstimulation

Goiter (large thyroid gland)

Graves Disease: Metabolic Dysfunction

Weight loss
Rapid heartbeat
Poor body temp regulation
Muscle weakness
Irritability

Systemic Autoimmune Disease

Immune response against many antigens
Impact many organs/tissues

Systemic: Rheumatoid Arthritis

Chronic joint inflammation
Common in women 40-60
Disrupt bone cell maintenance

Rheumatoid Arthritis: Rheumatoid Factors

IgM autoantibodies to IgG Fc receptors
Bind circulating IgG
Form immune complexes depositing in joints

Rheumatoid Arthritis: Deposits

Activate complement cascade
Prolonged inflammation
Joint tissue damage

Immunosuppression

Reduce immune response strength
Reduce symptoms of autoimmune diseases
No cure

Immunosuppression: Organ Transplant

Immune system attacks foreign organ
Immunosuppressants reduce rejection risk
Inhibit immune response against organ

Immunosuppressant: Corticosteroid

Anti-inflammatory
Kills T-cells

Immunosuppressant: Cytotoxic Drugs

Non-specifically block cell division

Immunosuppressant: Immunophilins

Block T-cell responses

Immunosuppressant: Lymphocyte-Depleting Therapies

Non-specifically kill T-cells

Immunosuppression Impact: Latent Infections

Inactive, hidden, dormant infections
Pathogen reactivation

Immunosuppression Impact: Opportunistic Infections

Pathogen translocation in host or from environment
Bacteria, viruses, parasites, fungi

Pneumocystis Jiroveci Pneumonia

Opportunistic fungal infection
PCP

Cryptococcosis

Opportunistic fungal infection
Cryptococcal disease
Lungs, spread to brain

Candidiasis

Opportunistic fungal infection
Thrush
Mouth, throat, vagina

Aspergillosis

Opportunistic fungal infection
Lungs

Tuberculosis

Opportunistic bacterial infection
Lungs

Mycobacterium Avium Complex

Opportunistic bacterial infection
MAC
Lungs, lymph nodes, entire body

Toxoplasmosis

Opportunistic parasitic infection
Skeletal muscle, myocardium (heart), brain, eyes

Cytomegalovirus

Opportunistic viral infection
CMV
Eyes, brain, other internal organs

Herpes Simplex Virus

Opportunistic viral infection
HSV
Skin, mouth, lips, eyes, genitals

Varicella Zoster Virus

Opportunistic viral infection
Chickenpox
Skin, internal organs (extreme)

Mononucleosis

Opportunistic viral infection
Epstein-Barr Virus
Lymph nodes, throat, salivary glands, liver, spleen, blood

Hypersensitivity

Excessive immune response

Type 1 Hypersensitivity

Immediate/anaphylactic

Type 1 Mediators

Allergens
IgE
Basophils
Mast cells

Type 1 MOA 1: Primary Allergen Exposure

Humoral response
Plasma cells secrete IgE
Bind mast cells and basophils

Type 1 MOA 2: Secondary Allergen Exposure

IgE cross-link with allergen
Basophil and mast cell release granules and vasoactive mediators
Vasodilation and smooth muscle contraction

Type 1 Reaction Time

Immediate: 15 mins
Longer: After 24h (rare)

Type 1: Allergic Rhinitis

Airborne allergens
Nasal irritation

Type 1: Atopic Dermatitis

Eczema
Skin eruptions and redness

Type 1: Asthma

Airways narrow, swell, produce excess mucous

Type 1: Hives

Urticaria
Itchy rash
Burn, sting, swell

Type 2 Hypersensitivity

Antibody-mediated cytotoxic

Type 2 Mediators

IgG
IgM
NK cells
Complement system

Type 2 MOA 1: Bind Antigen

IgG/IgM
Antigen Ex: Incompatible erythrocytes after blood transfusion

Type 2 MOA 2: Free Fc Region Activates

Classical complement: Opsonization and MAC (cell lysis)
Antibody-dependent cell-mediated cytotoxicity

Type 2 MOA 3: Cell Destruction

Cause excessive inflammatory response

Type 2 Reaction Time

Minutes to hours

Type 2: Drug-Induced Hemolytic Anemia

Non-specific antibiotic bind RBC membrane proteins
Induce complement-mediated lysis
Anemia from RBC rupture
Drug removal stops anemia
Ex: Penicillin

Type 2: Transfusion Reaction

Antigen (A/B) expression on RBC
No expression = antibodies
Blood type compatibility
O-: Universal donor, no A/B antigens
AB+: Universal recipient, no antibodies against A/B antigens

Type 3 Hypersensitivity

Immune-complex mediated

Type 3 Mediators

Antigen-antibody complexes
Neutrophils
Complement proteins

Type 3 MOA 1: Antibody-Antigen Reaction

Form immune complexes
Accumulate in tissue deposits

Type 3 MOA 2: Activate Complement

Neutrophil attraction to deposit site
Inflammation

Type 3 MOA 3: Lytic Enzymes

Released by neutrophils
Phagocytose immune complexes
Weaken cell membrane
Tissue damage

Type 3 Reaction Time

3-10h
Longer Development: Days, weeks

Type 3: Serum Sickness 1

Antitoxin administration containing foreign serum
Antitoxin: Antibody counteracting toxin

Type 3: Serum Sickness 2

Protein-specific antibody development after antiserum administration
Antiserum: Blood serum containing antibodies against specific antigen

Type 3: Serum Sickness 3

Antibodies and proteins form immune complexes
Accumulate in plasma filtration tissues
Pathogenesis of autoimmune diseases, hepatitis, malaria

Type 3: Serum Sickness 4

Symptoms after days to weeks
Subside after antigen breakdown

Type 4 Hypersensitivity

Cell-mediated/delayed-type

Type 4 Mediators

CD8+ cytotoxic T-cells
CD4+ helper T-cells
Macrophages
NO ANTIBODY MEDIATION

Type 4 MOA 1: T-Cell Activation

Initiate innate response
Release cytokines (especially TH1)

Type 4 MOA 2: Activation by Cytokines

Macrophages
Cytotoxic T-cells
Mediate cellular damage

Type 4 Reaction Time

Delayed
2-3 days

Type 4: Inflammatory Bowel Disease

Chronic digestive tract inflammation conditions
Autoimmune disease
Ulcerative colitis, Crohn's disease