Infection of compromised host and translation

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

• dysfunction of neutrophils due to chemotherapy, AIDS, complement dysfunction

• more likely to contract a disease and often to a more severe level than healthy individuals.

• rise due to modern medical treatments that have immuno-suppressive side- or direct effects

• are not only subject to the normal range of pathogens that infect healthy individuals

Definition of Immuno-compromised Host

• a side-effect of some anti-cancer drugs that kill rapidly proliferating cells and result in neutropenia

• organ transplant treatments directly suppress the immune system to enable survival of foreign tissue

examples of immunocompromised hosts

• nature and severity of infection - determined by the type and level of immuno-suppression.

• result of chemotherapy in cancer and organ transplant patients,

what effects compromised immune system

• Complement deficiencies

• phagocyte cell deficiencies

• born with it

primary innate systems

• Burns

• trauma

• major surgery

• catheterization

• foreign bodies (e.g. shunts, prostheses), obstruction

• due to environmental factors

secondary innate systems

• T-cell defects

• B-cell deficiencies

• severe combined immunodeficiency

• born with it

primary adaptive systems

• Malnutrition

• infectious diseases

• neoplasia

• irradiation

• chemotherapy

• splenectomy

• due to environmental factors

secondary adaptive system

• due to chronic granulomatosis disease (CDG)

• preventing body from synthesising cytochrome b245

• without it cells cant make reactive oxgyen species for phagocytosis

• neutrophils cannot kill phagocytosed pathogens

phagocytic cell dysfunction - primary innate defect

• defects in C4 or C2 stop the body from making classical C3 convertase.

• immune cells cant recognise foreign bacteria

• Associated with high frequency of extracellular infections

complement system failure - primary innate defect

• can disrupt mechanical and non-specific barriers

• trauma and surgery can breach skin and mucous membranes, leave areas poorly vascularised

• catheters allow microbes to bypass barriers

• urinary catheters reduce flushing of urethral mucous membrane

• foreign bodies like hip replacements and heart valves require surgical wounds and provide surfaces for microbes to colonise

examples of secondary immune defects

• damage mechanical barriers - (skin and mucous membranes)

• damaged capillary network

• Impacts local neutrophil function important for bacterial infections and general immune response

• Large burns can also cause water and electrolyte imbalances

• Burn wounds can quickly become colonised (within hours) particularly large burns

• bacteria can cause further damage to thickness of burn, migrate and cause systemic infections, poly-microbial (several types of bacteria involved)

burn wound infections - secondary innate defect

• either accidental or intentional

• wounds destroy the integrity of body surfaces

• disrupt blood flow and can seed microbes deep into tissues.

• Staphylococcus aureus is the most common cause of surgical wound infection

• germ is already living on the patient’s own skin, and when the surgeon makes an incision, it gets pushed deep into the tissue.

• maybe transferred to patient via a doctor

• Intravenous and peritoneal catheters – breach skin integrity and allow skin flora or patient or carer easy access to deeper site - Staphylococcus epidermidis bacteria stick to the plastic and build sticky film known as biofilm

Traumatic injury and surgical wounds

• no wound is created but catheter stops regular flushing of mucosal membrane of urethra

• infections usually derived from patient’s faecal or peri-urethral flora

urinary catheters

• prosthetic heart valves and hip, heart pace maker, CSF shunt - drains excess fluid from the brain or spine to another part of the body,

• Staphylococcus epidermidis is the most common pathogen

infection of plastic devices

• Respiratory tract – disruption to the ciliary escalator predisposes for infection e.g. cystic fibrosis

• Staph. aureus, Haemophilus influenzae, P. aeruginosa

• Obstruction to normal urine flow – Gram-negative bacteria from patients periurethral flora can ascend up urethra and cause infections • Septicaemia is an important complication

obstructions

• Defect in microenvironment assist in lymphocytes differentiation:

• No B cells – Burton-type agammaglobulinaemia

• No T cells – Di-George syndrome

defect in the microenvironment - primary adaptive defect

• non-functional recombinase enzyme prevents the b cells and t cells from forming clones to antigens

• severe combine immunodeficiency

defect in differentiation pathway - primary adaptive defect

• The weakened immune system pre-disposes individuals to more frequent and severe diseases

• Protein-energy malnutrition (PEM) – major form,

• Results in drastic effects on the structure of lymphoid organs,

• sluggish chemotactic response of phagocytes,

• lowered concentration of secretory and mucosal IgA

• Reduced affinity of IgG

• Low circulation T cells leading the inadequate cell-mediated response

malnutrition - secondary adaptive defencies

• infections themselves can be immunosuppressive

• Classic example – HIV infection leading to AIDS (acquired immunodeficiency syndrome)

• These infections can pre-dispose patient to other, opportunistic infections.

• AIDS – clinical definition of AIDS - presence of one or more opportunistic pathogens.

• Most of the pathogens are intracellular pathogens, as HIV destroys the cell-mediated response necessary to kill intracellular pathogens

• Brucella spp. Candida

infectious agents

• over-proliferation and dysfunction of lymphocytes can result in a compromised immune response

• cancer of lymphocytes

• Hodgkin lymphoma – caused by B cells only

• Non-Hodgkin lymphomas – caused by either B or T cells; most common lymphoma, 90%

• most due to uncontrolled b cell proliferation

Lymphomas - secondary adaptive defect

• A lack of circulating neutrophils is the primary reason for infections

• occurs in leukemic patients following bone marrow collaps and cancer patients undergoing chemotherapy – often temporary

Neutropenia due to granulocyte

• Treatments for cancer and other diseases may also cause immunosuppression:

• Cytotoxic agent – some chemotherapeutic agents can suppress the immune system

• It causes DNA crosslinking and subsequent apoptosis

• Corticosteroids - potent anti-inflammatory/immunosuppressive steroids

• reduces the number of circulating lymphocytes, monocytes and eosinophils and suppress leukocyte accumulation at side of infection

Chemotherapy

• Transplanted tissue from another person, unless identical twin, is seen the same way by the immune system as foreign

• The graft is subject to immune mechanisms as are other foreign substances like microorganisms

• Most common and successful transplant is blood ▪ RBCs is one cell type, have few antigens and no MHCs

• Major surface antigens are ABO and Rh blood groups

Transplantation - Foreign

• transplanted tissues/organs have multiple cells with many surface antigens and

• MHCs → very immunogenic

• common grafts: bone marrow, skin, cornea, kidneys, lung-heart, pancreas, liver

organ transplantation

• Pseudomonas aeruginosa - Gram-negative - produces a foul, green-pigmented discharge and necrosis; major Gram-negative bacteria

• Staphylococcus aureus – Gram-positive, coccus - major pathogen infecting burns, destroys granulation tissue (new connective tissue)

• Streptococcus pyogenes – Gram-negative coccus; highly transmissible, most common infection in the pre-biotic era,

opportunistic pathogens for burn wound infections

• transfer of tissue, the Graft, from one location to another location in the same body or to a completely different individual,

definition of graft

• person receiving the graft in a specific part of their body

definition of recipient

• Scale and rate of rejection depends on

• Sensitisation by pre-formed antibodies and immunological memory - whether their immune system has been exposed to this foreign material before.

• How “foreign” the graft is

• Level and rate of vascularisation for solid organs - if blood flow through organ body can detect the antigens more readily

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

Scale and rejection rate of graft

• Graft from one area to another on same individual – no immune response

• skin for burn

autograft

• Graft from one identical twin to another

• have same MHCs – no immune response

• kidney transplant

isograft

• Graft from one individual to another

• have different MHCs – reject

• liver transplant

• most common

• tissue is foreign even with careful matching

• Immune response will cause damage → require immunosuppression

allograft

• Graft from one species to another

• have different MHCs – reject e

• usually experimental

Xenograft

• as soon as graft is connected and blood from the recipient starts to flow through the donor organ (graft) the rejection starts

• pre-formed antibodies towards graft

• Antibodies from the recipient immediately interact with antigens on the capillaries of the graft and activate compliment (Hypersensitivity type II reaction)

• Inflammation ensues leading to vascular blockage and eventual failure of the graft

• very rapid and can occur within minutes

• Pre-formed antibody-mediated, no cell mediated immunity

Hyper-acute rejection

• Vascular and damage to the functional, essential tissue of an organ results usually after the first week

• Antigens seen for the first time by recipient immune system,

• no pre-formed antibodies to graft

• caused by poorly matched graft and host tissue antigens or insufficient immunosuppressant therapy

• T cell-mediated – intense infiltration of lymphocytes and macrophages, also involving antibodies

• Inflammation and tissue destruction including capillary destruction which stops blood and organ failure - causing graft rejection

acute rejection

• Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period, months to years

• Occurs in most solid ‘successful’ organ transplants: heart, kidney, lung, liver

• Low-level immune-mediated (T cell) damage of tissue with periodic cycles of regeneration leading to remodeling of tissue, disrupting function and resulting in fibrosis

• (lung transplantation) gradual loss of airway epithelium and thickening of airways leading to obstruction and eventual organ dysfunction

chronic rejection

• graft can reject the host

• host rejects the graft

• Happens in tissues/organs that contain many immune cells

• Bone marrow transplant – bone marrow is a source of immune cells

• Liver transplant – liver possesses a large populations of immune cells (lymphocytes, NK cells, macrophages)

• donor (graft) immune cells recognise host (recipient) MHC antigens as foreign as well vice versa

• Graft T cells undergo clonal expansion and mount an immune response against recipient tissues, (skin, intestine, liver)

graft vs host disease