immunodeficiency

Question 1

what is primary immunodeficiency?

Answer 1

Intrinsic genetic defects in the immune system. This can affect T & B cells (so antibody production), complement, and phagocytes. basically is absence or failure of NORMAL function in one or more elements of the immune system.

Question 2

what is secondary immunodeficiency? give 3 examples?

Answer 2

External factors that can deleteriously affect the immune system. Impair immune system from working properly. e.g. drugs, malnutrition, viral infection.

Question 3

what does immunodeficiency generally cause?

Answer 3

increased susceptibility to infection in individuals

Question 4

what are the 2 types of primary immunodeficiency?

Answer 4

1. Specific Immunodeficiency - abnormalities of T or B cells – this affects the adaptive immune system 2. Non-Specific immunodeficiency- abnormalities of phagocytes or complement – affects the innate immune system

Question 5

what are the 2 categories people with immunodeficiency can fall into? (___ infections)

Answer 5

pyogenic infections and opportunistic infections.

Question 6

what are pyogenic infections?

Answer 6

they involve pus formation. caused by defects in Ig, complement or phagocytes - patients are susceptible to recurrent bacterial infections

Question 7

give examples of bacteria which cause pyogenic infections?

Answer 7

H. Influenzae, S. Pneumoniae, S. Aureus

Question 8

what are opportunistic infections?

Answer 8

Defects in cell-mediated immunity (T cells). Susceptible to commensal organisms which usually live in harmony with the body. They start to cause pathology if there is immunodeficiency in T cells

Question 9

give examples of organisms which can cause opportunistic infections?

Answer 9

candida, viruses

Question 10

what are some primary B-cell deficiencies?

Answer 10

X-linked agammaglobulinemia (X-LA) IgA deficiency IgG subclass deficiency Immunodeficiency with increased IgM (HIgM) Common variable immunodeficiency (CVID) Transient hypogammaglobulinemia of infancy

Question 11

what tends to drive pyogenic infections?

Answer 11

B cell deficiencies (defects in B cell function)

Question 12

What are some features of patients with X-LA immunodeficiency disease? Who is more affected and why?

Answer 12

X-LA patients have no B cells, no tonsils, and produce very little IgG in serum (but have other Igs) generally affects males as the gene affected is on the X chromosome.

Question 13

how does X-linked recessive inheritance work? why does it affect males more than females?

Answer 13

Because females must receive a copy of the defective gene from BOTH parents to be affected as they have two X chromosomes. They can be carriers though.

Question 14

why is it unlikely that men affected with X-LA (recessive) will pass the gene on to offspring?

Answer 14

because most often the genetic diseases cause death in childhood.

Question 15

which is more common, X-linked dominant or X-linked recessive inheritance?

Answer 15

X-linked recessive.

Question 16

what is the cause of X-LA?

Answer 16

gene involved = defective btk gene. Defective btk gene that encodes a B-cell tyrosine kinase (which is crucial for cell signalling) btk is important in the maturation of B cells No B cell maturation (no transfer of B cells to plasma cells) SO, no IgG = poor Ab responses Sufferers get recurrent pyogenic infections

Question 17

what is the treatment / therapy of X-LA?

Answer 17

First 6-12 months of life children have protective maternal IgG. Then it’s repeated injections of gamma globulin throughout life (passive immunisation = short term protection) this can be difficult to tolerate and the disease has a poor prognosis.

Question 18

what is hyper-IgM immunodeficiency?

Answer 18

When someone is deficient in IgG and IgA but has hyper IgM (v large amounts of IgM) it is an X-linked recessive condition with mutations in CD40 CD40 is important for ‘class switching’ Normally this is where IgM turns to IgG (so Ab has same specificity) So a mutated CD40 means IgM cannot switch to IgG So more susceptible to pyogenic infections & autoimmune disease (form auto-IgM antibodies to neutrophils & platelets – second hit)

Question 19

What is the most common immunodeficiency?

Answer 19

IgA deficiency (1 in 700 caucasians)

Question 20

what is IgA immunodeficiency?

Answer 20

Failure in the terminal differentiation of B cells into plasma cells – the ones who produce IgA Individuals develop Type III hypersensitivity (immune complex) – several diseases experienced. Susceptible to pyogenic infections. Generally, an Ig deficiency will lead to pyogenic infection.

Question 21

what are some primary T cell deficiencies?

Answer 21

Severe combined immunodeficiency (SCID) Adenosine deaminase deficiency Purine nucleoside phosphorylase deficiency MHC class II deficiency DiGeorge anomaly Hereditary ataxia telangiectasia (AT) Wiskott-Aldrich syndrome (WAS)

Question 22

What is SCID?

Answer 22

severe combined immunodeficiency. individuals have no/poor T cell function. T cells help B cells to make antibodies so this also causes poor antibody production (poor humoral functions)

Question 23

what do people with SCID often suffer from?

Answer 23

commensal organism infections (e.g. oral candidiasis due to Candida albicans infection) - this can lead to systemic infection and high mortality. can’t form an immune response to typically commensal organisms.

Question 24

What is the epidemiology of SCID? What is the treatment?

Answer 24

More common in males - 50% of 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 (this involves obliterating all immune responses and get them replaced by donor cells) Bone marrow transplantation – usually sibling or parental transplantation to avoid graft rejection

Question 25

What is DiGeorge syndrome?

Answer 25

T cell deficiency because of an affected Thymus (important in T cell selection during development – so the defect causes poor selection) in foetal development. Several genes are involved.

Question 26

What are the distinctive facial features of DiGeorge syndrome?

Answer 26

1. Wide-spread eyes
2. Low set ears
3. Upper lip shortened
4. Abnormal aorta – also have cardiovascular disorders

Question 27

What is MHC II deficiency and what is the cause of it?

Answer 27

Deficiency in MHCII leads to failure to express MHC II antigens on APCs - so the deficiency is in how peptides get displayed to T cells.

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 production

Question 28

What do deficiencies in different complements increase susceptibility to?

Answer 28

Deficiencies in C3, Factor H and Factor I – increased susceptibility to pyogenic infections

Deficiencies in MAC increase in susceptibility to Neisseria infections (N. meningitides, N.gonorrhoeae

Question 29

What is the most common complement deficiency? What causes it?

Answer 29

Hereditary Angioneurotic Edema (HAE)

Question 30

What are the characteristics of HAE? What are some more serious consequences?

Answer 30

Patients have recurrent swelling.

more seriously:

intestinal - abdominal pains and vomiting

upper airways - choking and death due to the obstruction from swelling.

Question 31

What can defects in phagocytes affect?

Answer 31

can affect neutrophils or macrophages.

severe depletion in neutrophils (neutropenia) = severe pyogenic infections.

Question 32

which 2 genetic phagocytic defects are often fatal?

Question 33

what happens in chronic granulomatous disease (CGD)?

Answer 33

Defective NAPDH oxidase

(the rxn below needs NADPH Oxidase)

NADPH + 2O2 ——-> NADP+ + 2 O2- (free rad) + H+

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 & abscesses in liver, skin etc.

Question 34

how is CGD diagnosed?

Answer 34

It involves the inability of phagocytes to reduce the 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 (left)

In patients with CGD the dye remains yellow (right)

Question 35

What is leukocyte adhesion deficiency type 1 (LAD)?

Answer 35

Deficient for CD18 gene (integrin β chain)

Defective C’ Receptor 3 (CD18/CD11b) This binds bacteria opsonised with C3bi (complement receptor) – increase phagocytosis

Can not phagocytose opsonised bacteria –recurrent infections

ALSO

Defective CD18/CD11c – usually form a heterodimeric receptor

Important in leukocyte adhesion (CD18/CD11c binds to ICAM-1)

Phagocytes not able to bind to the endothelium and extravasate

Question 36

What is leukocyte adhesion deficiency type 2 (LAD)?

Answer 36

Defective receptors (CD15 – involved with rolling of leukocytes) that bind selections

Phagocytes can not roll on the endothelium

Question 37

what drugs can cause secondary immunodeficiency?

Answer 37

corticosteroids - glucocoticoids

anti-cancer therapy (chemotherapy and radiotherapy)

Question 38

what are the effects of corticosteroids (glucocoticoids)?

Answer 38

they cause significant changes in leukocytes in circulation after treatment

Question 39

how does radiotherapy cause immunosuppression as a side effect?

Answer 39

It causes strand breaks in the DNA (this is the aim of radio). This increases apoptosis and stops proliferation of cancer cells.

Targeted at cancer cells (high proliferation rates) but it also affects the bone marrow and lymphoidtissue

Stops immune cell production, proliferation and differentiation = v weakened immune system

Susceptible to organisms normally not pathogenic – especially commensal organisms (these are opportunistic infections)

(eg. Mucositis, mucosal infections (Candidainfections))

Question 40

how does chemotherapy cause immunodeficiency? which drugs are involved? (2)

Answer 40

Cyclophosphamide therapy: this is a pro-drug that is activated inside the body – enzymes cleave it to get the active form of drug.

When activated it cross-links DNA to stop cell proliferation and increase apoptosis. Mainly affects lymphocytes (B cells mostly). Causes a loss of cell-mediated and Ab production

Azathioprine

Azathioprine is converted to 6-mercaptopurine (a false base) in the body then metabolised to thioinosinic acid (a false base – and a chain terminator)

This gets incorporated into DNA & stops DNA replication & proliferation. It is targeted at tumour cells but will also affect haematopoietic stem cells.

Question 41

what are the effects of 5-Fluorouracil (brand names = Adrucil, Carac, Efudex and Fluoroplex)

Answer 41

Question 42

what drug is used in organ transplantation and what are its effects?

Answer 42

cyclosporin - it is used to dampen down the immune response.

An immunosuppressant drug used in transplants to reduce the activity of immune system and prevent organ rejection (also used in psoriasis, dermatitis, autoimmune urticaria)

Cyclosporin produced by fungus Beauveria nivea

Affects IL-2 production

Answer 43

Involves co-stimulatory molecules: CD28 on T cell bind to CD80/CD86 on APC

APC is displaying foreign peptides due to transplant rejection. The T cells recognise it as foreign - this secretes IL-2 which feeds back on its own receptors.

Activation: IL-2 is secreted & binds to IL-2R on T cells

Leads to: division, differentiation, effector functions, memory

Answer 44

When the MHC binds to the T cell receptor it causes an increase in calcium ions. This makes NFAT get phosphorylated and transcribed into IL-2.

Cyclosporin interacts with calcineurin and stops the activation of NFAT = IL-2 levels go down = doesn’t get secreted = receptor not activated = no response.

It’s good cos we don’t want t-cell response against foreign tissue but it also prevents response against bacteria.

Question 45

What is the most common cause of immunodeficiency? What damage does it do?

Answer 45

nutritional deficiency

malnutrition damages lymphoid tissue. it also causes:

Question 46

what are the 3 main nutrients people are deficient in?

Answer 46

Zinc

Reduction in delayed type IV hypersensitivity (cell-mediated reactions) Low CD4 & CD8 numbers

Impaired Ab responses (low plasma cell numbers)

Iron

Iron-dependent enzymes required for superoxide generation Low iron causes ineffective microbial killing by phagocytes

Vitamin B6 & folate

Deficiency reduce cell-mediated immunity, especiallylymphocyte Proliferation and Ab production

Question 47

what are some infections that HIV patients are susceptible to which healthy people could easily combat?

Answer 47

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 Cryptococcus neoformans – fungus(lives in soil) that causes meningitis

Cytomegalovirus – inflammation of brain & spinal cord

Question 48

what follows on from HIV?

Question 49

How does a HIV infection of lymphocytes occur?

Answer 49

Protein on the surface of HIV binds to CD4 and uses it as an anchor.

Has a conformational change which allows part of HIV molecule to bind to chemokine receptor.

It needs to interact with both CD4 and a chemokine receptor to gain entry into permissive cells and insert its genetic material and become infectious.

• X4 (T-cell tropic) – uses CXCR4
• R5 (M-cell tropic) – uses CCR5

2 stages are crucial.

in the symptomatic stage (early stages) - CCR5 predominates. As the infection proceeds, HIV uses CXCR4 (so becomes T cell tropic)

• CCR5 32degree deletion inhibits infection because the receptor is non-functional and rapidly degraded
• HTLV-1 Tax protein up-regulates CXCR4 & CCR5, this may accelerate HIV disease

Question 50

How long can it take before showing symptoms of HIV? What happens to the level of T cells throughout infection?

Answer 50

During primary infection - the number of T cells rapidly decline.

T cells then slightly recover and the number of viral particles drops rapidly (this stage is like a latent period and can last many yrs)

the virus then gets reactivated (unknown as to why!) and the number of T cells deplete so theres hardly any left.

it can take 10 years to show symptoms.

Question 51

what are some recurrent infetions that HIV patients present with?

Question 52

How can you monitor CD4 count?