Lec. 18 - Immunodeficiency & transplants

Define primary (congenital) immunodeficiency.

Define secondary (acquired) immunodeficiency.

Which one is common?

Primary (congenital): inherited in some aspect of the immune system

• Rare & diagnosed in children due to recurrent infections

  • Usually from a single gene mutation → 1 in 1200 births

Secondary (acquired): caused by some other factors

• Very common

  • Ex. HIV, drug treatment, malnutrition, age

Having an immunodeficiency can have an impact on susceptibility to internal flora, opportunistic infections, and normal pathogens. Define these.

Internal flora: usually harmless when in check → can become pathogenic (ex. Candida - yeast)

Opportunistic: Does not hurt healthy but are pathogenic to immunocompromised

• ex. staph aureus, aspergillus, toxoplasma gondii, cryptococcus neoformans

Normal pathogen: Immunocompromised are more easily infected

What is the typical infection amount in children (how many per year, what kinds of infections, acquired how)?

When should a primary immunodeficiency be considered?

Typical childhood infection: 5-6 per year

• URI, otitis media, gastroenteritis, strep pharyngitis

• Acquired at: Daycare, asthma/allergy, smoke exposure

Consider primary when: 2+ sever infections occur (pneumonia, bronchitis)

• Opportunistic & recurrent infections occur

• Family history of primary

The 5 primary (congenital) immunodeficiencies are: B-cell deficiency, T-cell deficiency, Combined immunodeficiency, Phagocytosis deficiency, and complement deficiency. What do these effect?

B-cell deficiency: Low levels of Ig’s → increase in infections that rely on Ab detection

• Hypogammaglobinemia & Agammaglobinemia

• Infections: encapsulated pyogenic bacteria → sinus, ear, lung, & GI infect.

  • Ex. Strep pneumonia & Haemophilus flu

T-cell deficiency: T-cell function → defect in T cell development/activation → loss of cell-mediated immunity (CTLs & Th cells)

• Infections: Intracellular (virus, fungi, bacteria), candidiasis (yeast), herpes, CMV, Malignancies (cancer)

Combined immunodeficiency: directly affects B & T cells

Phagocytosis deficiency: Defect in phagocytic cells → recurrent infections b/c no IgG or C3b opsonins

Complement deficiency: Defect in complement cascade

Bruton’s (X-linked) agammaglobunlinemia, Hyper-IgM syndrome, Selective IgA deficiency, and common variable immunodeficiency (CVID) are all primary B-cell deficiencies. List what gene is mutated and what they lead to.

Bruton’s (X-linked): Bruton’s tyrosine kinase (BtK) mutated

• Intracellular signaling defective → B cell development failure

  • OR B-cell receptor mutated → autosomal recessive gene

• Causes: recurrent infections after 6months old → mom Ab’s leave baby

  • Normal T cell amount & function

• Boys affected

Overall defect: B cells fails to develop

Hyper-IgM: Mutation in CD40/CD40L

• Th-B interaction failure → No Ab class-switching

• X-linked and/or autosomal

Overall defect: T cell issue

Selective IgA → lack of IgA: Unknown genetic cause

• Infections at mucous membranes → GI & respiratory

• Most common PID (primary immunodeficiency)

Common Variable (CVID): conditions w/ various etiologies

• Defect in plasma cell differentiation

  • Hypogammaglobinemia: low IgG & IgA

• Present in 20s/30s: increased freq. of shingles, malabsorption, lymphoproliferative disorders

Overall defect: Plasma cell problem

DiGeroge syndrome and Chronic mucocutaneous candidiasis are primary T-cell deficiencies. Describe what these affect and what it leads to.

DiGeorge: Deletion on chromosome 22 → decreased T cells

• Congenital thymic aplasia (hypoplasia) → leads to cleft palate & heart defects

• Viral, fungal, & bacterial infections

Overall defect: Plasma cell issue

Chronic mucocutaneous candidiasis: Unknown cause

• Failure to respond to C. albicans Ag’s

Severe combined immunodeficiency syndrome (SCID), X-SCID, Adenosine deaminase (ADA) deficiency, and Wiskott-Aldrich syndrome (WAS) are all primary combined (B & T cell) immunodeficiencies. Describe each of these.

SCID: Caused by at least 20 genes

• Low or absent T & B cells → No Ab response to vaccines

  • shows up in early infancy → fatal if untreated

• Symptoms: failure to thrive, opportunistic infections, thrush

  • Treatment: BM transplant

SCID-X: Most common SCID (affects boys) → mutated IL-2Ry

• Lack of T-cell & NK cell maturation & non-functional B cells

ADA: Autosomal recessive

• Lack of purine metabolism enzyme = toxic accumulation of purine

Wiskott-Aldrich (WAS): X-linked (boys affected)

• T cell defects ; Humeral: low IgM and high IgE

• Symptom triad: Immunodef., Eczema, Thrombocytopenia

  • Prolonged bleeding, low hemagglutinins, increased alpha-fetoprotein

Congenital & cyclic neutropenia, Leukocyte adhesion deficiency (LAD), and Chronic granulomatous disease (CGD) are all primary phagocytic immunodeficiencies. Describe them.

Congenital & cyclic neutropenia: Mutated neutrophil elastase gene

• Neutrophils can’t enter tissue → recurrent bacterial infections

Leukocyte adhesion def. (LAD): Mutations in leukocyte adhesion molecules

• Leukocytes can’t slow down = can’t enter tissue → adhesion & extravasation deficiency

Chronic granulomatous (CGD): Mutation in NADPH oxidase complex

• Defect in ROS → WBCs can phagocytose but can’t kill bacteria

Complement deficiency is also a primary immunodeficiency. What does a deficiency in early complement (C1, C4, and C3) allow for infections of? Late complement (MAC)?

Early complement: encapsulated bacteria infections - autoimmunity

Late complement: Neisseria infections

What are general screening tests for primary immunodef. (PID)?

1. CBC w/ differential: detects for WAS (thrombocytopenia) & reduced lymph counts → B or T cell defect

2. B cell tests: Ab monitoring → ex. Ab response to vaccines

3. T cell tests: Type IV hypersensitivity reactions (TB?)

4. Complement: CH50

5. Flow cytometry: Neutrophils

Flow cytometry, genetic testing, and serum protein electrophoresis are all specific screening tests for PID. What do these detect?

Flow: PB leukocytes w/ fluorescent labeled-Ab against CD markers (that you are checking).

Genetic testing: checks for known mutations

SPE: Checks for Ab’s → B-cell defects

Secondary immunodef., are more common than PIDs. What should be considered to differentiate from primary vs. secondary deficiency?

Consider patient history

• ex. splenectomy increases pyogenic bacterial infections (common in PID)

  • Renal disease: hypogammaglobulinemia (which would indicate B-cell defect in PID if we didn’t have the history)

Iatrogenic immunodeficiencies are caused by immunosuppressive drugs or splenectomy. Drugs: Cytotoxic, Corticosteroids, Cyclosporine, Radiation do what to the immune system? How does splenectomy affect the immune system?

• Cytotoxic drugs: Used for cancer treatment → kills rapidly dividing cells including BM leukocytes

• Corticosteroids: Wide immunosuppressive & anti-inflammatory effect

• Cyclosporine: anti-rejection drug → inhibits proliferation of Th cell

• Radiation: Kills many cells & rapidly dividing cells

• Splenectomy: increases infection susceptibility → especially to strep pneumonia

Define Autograft.

Tissue transplant from one area of body to another (tissue from same individual → no rejection).

Define Allograft.

Tissue transplant from one person to another (can be rejected).

Define Syngenic graft.

Tissue transplant between identical twins (doesn’t require anti-rejection drugs)

Define Xenograft.

Tissue transplant between different species (ex. animal kidney in human)

Define transplant rejection.

Cell & Ab-mediated reactions against an Allograft

In an allograft (transplant from one person to another), the immune system can recognize the foreign tissue through two methods: Direct recognition and indirect recognition. How do these work and what does it trigger?

Direct recognition: host T cell recognizes foreign MHC on allograft cells

• CD8+ T cell see MHC I → CTLs attack foreign cells

• CD4+ T cells see MHC II → promotes inflammation

Indirect recognition: host APC goes to foreign tissue & gets Ag → shows it to CD4+ T cell

• CD4+ T cell → promotes inflammation

• B cells secrete anti-graft Ab’s

What happens to an organ if it is rejected?

Death of grafted parenchymal cells & endothelium

• Thrombosis & graft ischemia (O2 deprived)

A type of transplant rejection is hyperacute rejection. What is this? What are some ways a recipient can already have Ab’s to the donor. How common is this?

Hyperacute: occurs within minutes to hours after transplant due to preformed anti-donor Ab’s → surgeon usually sees after vascular anastomosis

• Pregnant women sensitized to HLA due to birth

• Sensitization from blood transfusion

• Sensitization from prior organ transplant

Rare → b/c of screening for anti-HLA & cross-match testing

Other types of transplant rejection are acute and chronic rejection. Describe these.

Acute: Occurs days-weeks in non-immunosuppressed : months-years in immunosuppressed

• Cell or humeral

Chronic: months-years after

• T-cell mediated → results in parenchymal fibrosis & arteriosclerosis (organ hardening)

Hematopoietic stem cell (HSC) transplant is a therapy for: malignancies (cancer), aplastic anemia, PID, and thalassemia. What all acts as a donor? How is it received?

Donor: BM, PB after growth factors/cytokine induction, umbilical cord

Received: BM ablated w/ chemo, Graft infused into PB, Stem cells in BM replenish host

Graft versus host disease and Immune deficiency are both complications of HSC transplant. What causes graft-versus-host disease and where does it occur in? What causes immune deficiency?

Graft-versus-host: Donor T cell attacks recipient cells

• Can occur in blood rich organs (ex. spleen & liver)

• Symptoms: Skin rash, GI irritation, Mucosal involvement

Immune def: BM ablation makes recipient immunocompromised

To prevent organ rejection HLA matching is conducted prior to transplant. What is HLA phenotyping? HLA genotyping?

HLA phenotyping: Complement dependent cytotoxicity (CDC)

• Antisera incubated w/ lymphocytes → complement added → Bound Ab’s activate & kill cells → dye marks live vs. dead cells → phenotype = dead cells

HLA genotyping: PCR amplification of HLA genes

Another way to prevent organ rejection is through immunosuppressive therapy. How do these works and what medications are used?

Used in all transplants BUT identical twin transplants

• Cyclosporine & FK506 → suppress T-cell immunity

• Medications: Corticosteroids, MAb’s

• Be aware of global immunosuppression

Are transplant recipients ever not immunosuppressed?

They will always be immunosuppressed