Infections of the compromised host + Transplantation

Question 1

Define what an immunocompromised host is + what are oppurtinistic pathogens?

Answer 1

A person that is missing or has a defect in one or more components of their natural immune system

> Immunocompromised individuals is on the rise due to modern medical treatments, examples:

• Side effect of some anti-cancer drugs results in neutropenia
• organ transplant treatments suppress the immune system to enable survival of foreign tissue

Immunocomprised people are subject to oppurtunistic pathogens that normally do not cause disease.

Question 2

Define primary and secondary immune defects leading to immunocompromise

Answer 2

Primary immunodeficiency: inherited or through exposure in utero, environmental factors –> RARE

Secondary/acquired immunodeficiency: Due to an underlying diease state or as a result of a treatment (environmental influence)

Question 3

Describe the major types of primary immune defects (for both innate and adaptive)

Answer 3

Innate Immune defects (primary):

• Phagocytic cell dyfunction (Neutrophils cannot kill phagocytosed pathogens) –> Chronic granulomatosis disease)
• Complement system failure (Inability to generate classical C3 convertase)

Adaptive Immune defects (primary):

• Major congential abnormalities (No B cells = Bruton-type agammaglobulin + No T cells = DiGeorge syndrome) –> B cell antibody and T cell receptor variable region for antigen recognition doesnt form
• Esentially T-cell defects and B-cell deficiencies –> severe combined immunodeficiency

Question 4

Describe the major types of secondary immune defects (for both innate and adaptive)

Answer 4

Innate Immune defects (secondary):

• burns (damage mechanical barriers (skin and mucous mebranes) –> impacts local neutrophil function important for bacerial infection)
• trauma (disrupt blood flow, seed microbe deep into tissues)
• major surgery (Staphylococcus aerus is the most common cause of surgical wound infection )
• catherization (urinary catheters reduce flushing of urethral mucous membranes)
• foreign bodies (like hip replacement and heart valves –> provide surfaces for for microbes to colonise) –> Staphylococcus epidermidis is the most common pathogen
• obstruction (stasis predisposes individuals to infection)

Adaptive Immune defects (secondary)

• malnutrition (most important cause of acquired immunodeficiency worldwide) –> protein-energy malnutrition(PEM) = major form

> effects structure of lymphoid organs, sluggish response of phagocytes

• infections agents (infections themselves can be immunosuppresive) –> suppress the immune system = most of the pathogens are intracellular

> HIV infection leading to AIDS (Aids = presence of one or more oppurtunistic pathogens)

>Measles, mumps, tuberculosis

• Neoplasia of the lymphoid tissue (overproliferation and dysfunction of lymphocytes can result in a compromised immune response)

> Hodgkin lymphoma (caused by B cells only)

>Non-Hodgkin lymphoma (caused by either B or T cells) –> most common lymphoma

• Chemotherapy

> Cytotoxic agent (chemotherapeutic agent suppresses the immune system) –> apoptosis

>Corticosterioids (potent anti-inflammatory and immunosuppresive steroids) –> reduces number of lymphocytes, monocytes, eosinophils circulating around

Question 5

What are oppurtunistic pathogens? Provide some examples

Answer 5

A microorganism that normally does not harm its host but can cause disease when host’s resistance is low

• Pseudomonas aeruginosa (Gram-negative, rod; produces a foul green-pigmented discharge and necrosis)
• Staphylococcus aureus (Gram-positive, coccus; major pathogen infecting burns
• Streptococcus pyogenes (Gram-negative, coccus; highly transmissible, most common infection in pre-biotic era, still a problem)

Question 6

What are grafts and why may they be a rejected by a recipients immune system. How to reduce the risk of graft rejection?

Answer 6

Grafts are tissues that are transplanted from one location to another. Common grafts include:

• bone marrow
• skin
• cornea
• kidneys
• lung/heart
• pancreas
• liver

Scale and rate of rejection depends on:

• Sensitisation by pre-formed antibodies and immunological memory
• How foreign the graft is (human versus animal)
• Level and rate of vascularisation of solid organs

To avoid/reduce risk of graft rejection, the graft and recipient tissue antigens must be closely matched and ongoing immunosuppression is required

Question 7

Define autograft, isograft, allograft and xenograft, and describe the natural outcome of these grafts.

Answer 7

Autograft: Graft from one area to another on same individual (no immune response –> e.g skin for burn)

Isograft: Graft from one identical twin to another, have same MHCs –> no immune responses e.g kidney transplant

Allograft: Graft from one person to another (have different MHCs –> reject e.g. liver transplant

Xenograft: Graft from one species to another; have different MHCs –> reject e.g. usually experimental

Allografts are the most common:

• Tissue is foreign even with careful matching
• Immune response will cause damage –> require immunosuppression

Question 8

Describe the three possible clinical outcomes of tissue rejection, including the general immune mechanisms involved.

Answer 8

Hyperacute rejection (ANTIBODY MEDIATED): occurs through preformed antibodies from previous transplant

• E.g. incorrect blood transfusion(ABO:preformed antibodies –> already present , second pregnancy (Rh antigens)
• Antibodies from recipient interact with antigens on graft and activate complement –> hypersensitivity type II reaction
• Inflammation causes vascular blockage and grafts fail
• Occur within minutes

Acute rejection (CELL MEDIATED): result of adaptive immune system developing against antigen –> takes about one week

• Due to poorly matched graft and host tissue antigens or insufficient immunosuprresant therapy
• T-cell mediated, infiltration of lymphocytes and macrophges
• Inflammation and tissue destruction occurs –> stops blood flow and organ failure

Chronic rejection (CELL MEDIATED): happens over months-years resulting in tissue modelling and fibrosis –> organ dysfunction

>occurs in most succesful organ transplants

>Low level immune-mediated (T cell) dmage of tissue with cycles of regeneration leading to remodelling of tissue, disrupting function –> fibrosis

e.g lung transplantation (loss of airway epithelium and thickening of airways)

Question 9

Explain Graft-Versus-Host-Disease (GVHD)

Answer 9

Grafts reject the host

> Happens in tissue/organs that contain many immune cells

Examples:

• bone marrow transplant –> bone marrow is a source of immune cells
• liver transplant –> liver posseses a large population of immune cells e.g. lympocytes, NK cells, macrophages

Donor (graft) immune cells recognise host (recipient) MHC antigens as foreign as well as vice vera

> Graft T cells undergo clonal expansion and mount an immune response against recipient tissues, including skin, intestine, liver