Immunodeficiency Flashcards
Primary immunodeficiency
Intrinsic genetic defects in immune system
Affects T & B cells (Ab production), complement,
phagocytes
Absence or failure of NORMAL function in one or more elements of immune system
Immunodeficiency causes > susceptibility
to infection in individuals
-specific or non-specific
Secondary immodeficiency
External factors that can deleteriously affect immune system
Drugs (hormones, cancer therapy, transplants), Malnutrition, Viral infection, burns
Primary immunodeficiency: specific immunodefiency
Abnormalities of T or B cells - Adaptive Immune System
Primary immunodeficiency: non-specific immunodefiency
Abnormalities of phagocytes or complement - innate immune system
People with immunodeficiencies fall into 2 categories:
- Defects in Ig, C’, phagocytes – susceptible to recurrent
bacterial infections (H. Influenzae, S. Pneumoniae, S.
Aureus)
-termed: Pyogenic Infections – pus formation - Defects in cell‐mediated immunity (T cells)
-susceptible to commensal organisms (eg. Candida Candida, Viruses)
-termed: Opportunistic Infections
B-cell deficiencies
Have defects in B cell function - pyogenic infections
- X-linked Agammaglobulinemia (X-LA)
- IgA deficiency
- Hyper-IgM Immunodeficiency
X-linked Agammaglobulinemia (X-LA)
B-cell deficiency
Like many immunodeficiencies - gene affected on X chromosome (affects males)
Have no B-cells, no tonsils, little IgG in serum (but have other Igs)
X-linked recessive inheritance
Occurs more frequently in males because only have one X chromosome. Females must receive copy of defective gene from BOTH parents to have recessive disease. Females are CARRIERS if they have one copy of defective gene. The other normal gene is dominant (ie. it works) X‐linked recessive genes passed from female carriers to their ill sons and carrier daughters. Ill males would have to father a daughter to pass on gene. Unlikely because genetic diseases often cause death in childhood.
X-linked dominant inheritance
Less common than X‐linked recessive
Dominant Gene carried on the X‐
chromosome and only ONE copy of
gene is sufficient to cause the disorder.
(ie. Defective gene is dominant)
Mother has mutated gene and passes it onto her offspring
50% of children (25% male, 25% female)
will have the disease
50% will be unaffected
The sons of man with X-linked dominant disorder will not be affected, but his daughters will all inherit condition
X-linked Agammaglobulinemia (X-LA) mechanism
Defective btk gene that encodes a B cell tyrosine kinase
btk Important in maturation of B cells
No B cell maturation SO no IgG – poor Ab responses
First 6‐12 months of life have protective maternal IgG
Get recurrent pyogenic infections
X-linked Agammaglobulinemia (X-LA) therapy
Repeated injections of gamma-globulin throughout life
Hyper-IgM Immunodeficiency
Deficient in IgG and IgA but hyper IgM (large amounts of IgM)
X‐linked recessive recessive condition condition with mutations mutations in CD40
Hyper-IgM Immunodeficiency mechanism
CD40 important for ‘class switching’ Where IgM turns to IgG (Ab has same specificity) So can not switch from IgM to IgG Susceptible to pyogenic infections & autoimmune disease (form auto‐IgM antibodies to neutrophils & platelets)
IgA deficiency
Most common immunodeficiency (1 in 700 Caucasians)
Failure in terminal differentiation of B cells to plasma cells
Individuals develop Type III hypersensitivity (immune complex)
Susceptible to pyogenic infections
T cell deficiencies
Opportunistic infections
- severe combined immunodeficiencies (SCID)
- DiGeorge Syndrome
- MHC II deficiency
severe combined immunodeficiencies (SCID)
Individuals with no or poor T cell function
BUT ‐ B cell function depends on T cell function
SO ‐ T cell deficient individuals have poor T cell and
humoral functions
People with SCID suffer from
commensal organism infections
eg. Oral Candidiasis due to
Candida albicans infection
SCID in the population
SCID have very few lymphocytes
SCID more common in males‐ 50% cases X‐linked (due to
defective IL‐2R gene)
But also other genetic abnormalities that are not X‐linked
SCID is incompatible with life and infants die within first 2
years of life without bone marrow transplantation
Bone marrow transplantation – usually sibling or parental
transplantation to avoid graft rejection
DiGeorge Syndrome
T cell deficiency because of affected thymus in foetal development
DiGeorge distinctive features
Facial features:
- Wide-spread eyes
- Low set ears
- Upper lip shortened
- Abnormal aorta - also have CV disorder
MHC II deficiency
Deficiency in MHCII leads to failure express MHC II antigens on APC
Because CD4+ cells require MHCII for positive selection in the thymus, Infants deficient in MHC II
have no CD4+ cells
Lack of CD4 cells leads to deficiency in Ab
Complement deficiencies
Deficiencies in C3, Factor H and Factor I – > susceptibility to pyogenic infections
Deficiencies in MAC > in susceptibility to
Neisseria infections (N. meningitides, N. gonorrhoeae)
Most common is:
Hereditary Angioneurotic Edema (HAE)
Hereditary Angioneurotic Edema (HAE)
Most important C’ deficiency
C1 inhibitor‐ inhibits activation of C1 ( first initiator of C’
pathway)
Inhibits C’ and elements of the kinin/clotting system
Allows severe oedema due to plasma leakage leakage
Patients have recurrent swelling
Intestine - abdominal pains and vomiting
Upper airways - choke and death due to obstruction
Defects in phagocytes
Can affect Neutrophils or Macrophages
Severe depletion in neutrophils (neutropenia) results in severe pyogenic infections
2 genetic defects defects that are often fatal:
1. Chronic Granulomatous Disease (CGD)
2. Leukocyte Adhesion Deficiency (LAD)
Chronic Granulomatous Disease (CGD)
Defective NAPDH oxidase
Phagocytes CANNOT form superoxide ions & H2O2 (ROS‐ Reactive
Oxygen Species) to kill microbes
Organisms remain alive in phagocytes – persistent intracellular infections &
granulomas form
Infections with S. Pneumoniae &
abbesses in liver, skin etc.
Diagnosis of CGD
Inability of phagocytes to reduce nitroblue tetrazoliium (NBT) dye
NBT is pale yellow when taken up by phagocytes during phagocytosis.
In healthy phagocytes it is reduced by ROS to a purple colour
In pxs with CGD the dye remains yellow
Leukocyte Adhesion Deficiency (LAD) types
LAD type 1
LAD type 2
LAD type 1
Deficient for CD18 (integrinβ chain)
Defective C’ Receptor 3 (CD18/CD11b) - this binds bacteria
opsonised with C3bi – increase phagocytosis
Can not phagocytose opsonised bacteria – recurrent infections
ALSO
Defective CD18/CD11c
Important in leukocyte adhesion (CD18/CD11c binds to ICAM‐1)
Phagocytes not able to bind to the endothelium and
extravasate
LAD type 2
Defective receptors (CD15) that bind selections Phagocytes can not roll on endothelium
Secondary immunodeficiency - drugs
Corticosteroids - glucocorticoids
Anti-cancer therapy
Secondary immunodeficiency - drugs - corticosteroids - glucocoirticoids
Significant changes in leukocytes in circulation after treatment **
Lymphocytopenia ‐ T cells (especially CD4) affected more than B cells
Monocytopenia – very quick (2h) but back to normal by 24h
Neutrophillia – due to release of mature neutrophils from the bone marrow
Repeat dose – leads to low lymphocytes, lack of Ab and defective cytokine synthesis
Secondary immunodeficiency - drugs - anti-cancer therapy
Immunosuppression
Radiotherapy
-causes strand breaks in DNA
> apoptosis and stops proliferation
-targeted at cancer cells (high proliferation rates) but also affects bone marrow and lymphoid tissue
-stops immune cell production, proliferation and
differentiation
-susceptible to organisms normally not pathogenic – especially
commensal organisms
(eg. Mucositis, mucosal infections (Candida))
Secondary immunodeficiency - drugs - anti-cancer therapy - radiotherapy
Immunosuppression
-causes strand breaks in DNA
> apoptosis and stops proliferation
-targeted at cancer cells (high proliferation rates) but also affects bone marrow and lymphoid tissue
-stops immune cell production, proliferation and
differentiation
-susceptible to organisms normally not pathogenic – especially
commensal organisms
(eg. Mucositis, mucosal infections (Candida))
Secondary immunodeficiency - drugs - anti-cancer therapy - chemotherapy drugs
Cyclophosphamide
Azathioprine
5-Fluorouracil (brand names Adrucil, Carac, Efudex and Fluoroplex)
Secondary immunodeficiency - drugs - anti-cancer therapy - chemotherapy - cyclophosphamide
-pro‐drug activated inside body
-when activated it cross‐links DNA to stop cell proliferation and >
apoptosis
-mainly affects lymphocytes (B cells mostly)
-loss of cell‐mediated mediated and Ab production
Secondary immunodeficiency - drugs - anti-cancer therapy - chemotherapy - Azathriopine
Azathioprine is converted to 6‐mercaptopurine in body then
metabolised to thioinosinic acid (a false base – chain terminator)
-this gets incorporated into DNA & stops DNA replication and proliferation
Secondary immunodeficiency - drugs - anti-cancer therapy - chemotherapy - 5-Fluorouracil
Pyrimidine analog that works through inhibition of thymidylate synthase
(this methylates deoxyuridine monophosphate (dUMP) into thymidine
monophosphate (dTMP))
SO – 5FU blocks thymidine synthesis, which is a nucleotide required for
DNA replication
5FU gets incorporated into DNA and RNA and induces cell cycle arrest
(in S‐phase) and apoptosis
Affects T and B cells & NK cell numbers
Organ transplantation - cyclosporin
An Immunosuppressant drug used in transplants to reduce activity of
immune system and prevent organ rejection (also used in psoriasis,
Cyclosporin
dermatitis, autoimmune urticaria)
Produced by fungus Beauveria nivea
Particularly affects T cells by affecting IL-2 production
Organ transplantation - T cell Ag recognition and activation ***
Involves co‐stimulatory molecules
CD28 on T cell bind to CD80/ CD86 on APC
This is required for full activation
Activation: IL-2 secreted and bind to IL-2R on T cells
Leads to: division, differentiation, effector functions, memory
Organ transplantation: Rapamycin (also known as Sirolimus) ***
immunosuppressant drug used to prevent rejection in organ transplantation; it
is especially useful in kidney transplants because of low toxicity
Malnutrition
Worldwide nutritional deficiency most common cause of
immunodeficiency
Malnutrition damages lymphoid tissue
‐lymphoid atrophy
‐thymus severely affected in children – T cell abnormalities
‐reduced number of CD4+ cells
‐reduced sIgA (mucosal infections)
‐reduced C’ levels
‐reduce microbial killing by phagosomes
Numerous enzymes in immune system require co‐factors
Malnutrition - zinc
Reduction in delayed type IV hypersensitivity (cell‐mediated)
Low CD4 & CD8 numbers
Impaired Ab responses (low plasma cell numbers)
Malnutrition - iron
Iron‐dependent enzymes required for superoxide generation
Low iron causes ineffective microbial killing by phagocytes
Malnutrition - vitamin B6 and folate
Deficiency reduce cell‐mediated immunity, especially lymphocyte
Proliferation and Ab production
Acquired Immune Deficiency Syndrome (AIDS)
Due to Human Immunodeficiency Virus (HIV) infection
-infection of lymphocytes **
HIV - how to monitor CD4 count
Flow cytometry
HIV -Recurrent infections
- Oral candidiasis
- Varicella‐Zoster infection infection (Shingles)
- Herpes Simplex Virus (oral & genital)
- Cutaneous skin infections
HIV - more serious infections
Kaposi’s Sarcoma‐ Tumour of endothelial cells – widespread in skin, mucous, visceral
(gut & lungs) and lymph node disease occurs
Pneumonia‐ Due to Pneumocystis jirovecii ( formally P. carinii), Mycobacterium
tuberculosis & fungal infections
Enteric bacteria – cause weight loss
Toxoplasmosis – protozoal infection – causes brain & neurological problems problems
Cryptococcus neoformans – fungus that causes meningitis
Cytomegalovirus – inflammation of brain & spinal cord
HIV
•HIV needs to bind to CD4 and a chemokine HIV needs to bind to CD4 and a chemokine
receptor to gain entry into permissive cells
•X4 (T-cell tropic) cell tropic) – CXCR4
•R5 (M-cell tropic) – CCR5
•In asymptomatic stage CCR5 predominates - As infection proceeds HIV uses CXCR4
•CCR5 Δ32 deletion inhibits infection because
the receptor is non-functional and rapidly
degraded
•HTLV-1 Tax protein up 1 Tax protein up-regulates CXCR4 &
CCR5, may accelerate HIV disease
HIV infects and kills T h (CD4) cells by several mechanisms
Anti‐HIV antibodies produced by proteins in HIV envelope change
shape due to mutations so Ab not effective – a bit like continually
moving the goal posts
Can take 10 years to show symptoms
