Week 3: Defensive Failure

Question 1

What are primary immune deficiencies?

Answer 1

Primary Immune Deficiency (PI) causes children and adults to have infections that come back frequently or are unusually hard to cure. Primary immuno-deficiencies are caused by genetic defects that lead to blocks in the
maturation or function of different components of the immune system.

Question 2

What common immune functions are impaired in primary immediately deficiencies?

Answer 2

Depending on the genes concerned, the following functions may be impaired:
􀁸 T- and B cell function: severe combined immunodeficiency (SCID).
􀁸 Global or partial B cell response.
􀁸 Phagocytosis.
􀁸 Complement functions.

Question 3

Signs of primary immunodeficiency in children

Answer 3

Children up to age 18. Child has two or more of:

1 Four or more new ear infections within 1 year
2 Two or more serious sinus infections within 1 year
3 Two or more months on antibiotics with little effect
4 Two or more pneumonias within 1 year
5 Failure of an infant to gain weight or grow normally
6 Recurrent, deep skin or organ abscesses
7 Persistent thrush in mouth or fungal infection on skin
8 Need for intravenous antibiotics to clear infections
9 Two or more deep-seated infections including septicemia
10 A family history of Primary Immunodeficiency

Question 4

Signs of primary immunodeficiency in adults

Answer 4

Adults: two or more of these signs:

1 Two or more new ear infections within 1 year
2 Two or more new sinus infections within 1 year, in the absence of allergy
3 One pneumonia per year for more than 1 year
4 Chronic diarrhea with weight loss
5 Recurrent viral infections (colds, herpes, warts, condyloma)
6 Recurrent need for intravenous antibiotics to clear infections
7 Recurrent, deep abscesses of the skin or internal organs
8 Persistent thrush or fungal infection on skin or elsewhere
9 Infection with normally harmless tuberculosis-like bacteria
10 A family history of Primary Immunodeficiency

Question 5

What is Severe Combined Immune Deficiency (SCID)?

Answer 5

Severe Combined Immune Deficiency (SCID) is a potentially fatal primary immunodeficiency in which there is combined absence of T-lymphocyte and B-lymphocyte function. This usually results in the onset of one or more serious infections within the first few months of life.

Unless these defects are corrected, the child will die of opportunistic infections before their first or second birthday. Children affected by SCID can also become ill from live viruses present in some vaccines.

Question 6

How is Severe Combined Immune Deficiency (SCID) treated?

Answer 6

Effective treatments, such as bone marrow and stem cell
transplantation, exist that can cure the disorder.

The future holds the promise of gene therapy for several more types of SCID.

Question 7

Which type of SCID involved markedly decreased T cells, normal or increased B cells and reduced serum Ig?

Answer 7

X Linked SCID - cytokine receptor common Amma chain gene mutations, defective T cell maturation due to lack of IL-7 signals

Question 8

Which type of SCID involves a progressive decrease in T and B cells (mostly T)?

Answer 8

Autosomal recessive SCID

Question 9

What is X Linked agammaglobulinemia?

Answer 9

A primary immune deficiency related to Defects in B Cells

A defect in the Bruton tyrosine kinase (btk) gene means that pre-B cells in the bone marrow fail to expand resulting in fewer B cells and immunoglobulins.

Question 10

Give an example of an inherited condition that results from genetic defects that cause dysfunctional development of the B cell lineage or immunoglobulins themselves?

Answer 10

X Linked agammaglobulinemia.

pre-B cells in the bone marrow fail to
expand resulting in fewer B cells and immunoglobulins.

Question 11

Give an example of an inherited condition that results from genetic defects that cause defective antibody production.

Answer 11

X linked hyper IgM syndrome.

Common variable immunodeficiency (CVID).

IgA deficiency - multiple gene loci defects.

Question 12

What is X linked hyper IgM syndrome?

Answer 12

A primary immune deficiency related to Defects in B Cells

Mutations in the X chromosome encoding CD40 ligand, that is involved in the mediation of T cell dependent activation of B cells. This leads to defective T cells dependent B cell responses, ultimately causing defective B cell heavy chain isotype switching so IgM is the major serum antibody.

Question 13

What is Common variable immunodeficiency (CVID)?

Answer 13

A primary immune deficiency related to Defects in B Cells

Genetic defects lead to a reduction in the serum levels of IgG, IgA and IgM and a poor antibody response to infection.

Question 14

What is the mechanism underlying Chronic Granulomatous Disease?

Answer 14

Granulocytes and monocytes carry out their normal functions of phagocytosis, but are incapable of killing the organisms they phagocytose due to a deficiency of the enzyme NADPH oxidase, required to produce the “oxidative burst”. Patients are susceptible to various microorganisms which are normally of low virulence, particularly with Staphylococcus aureus and gram-negative bacteria.

Question 15

What is Chediak-Higashi Syndrome?

Answer 15

Chediak-Higashi syndrome is caused by the deficiency of a vesicle transport protein, so that phagosomes fail to fuse with lysosomes. Consequently, the cells fail to destroy ingested microbes.

Question 16

Defects in the mannan-binding lectin (MBL) and alternative pathway lead to…

Answer 16

an increased susceptibility to infections, particularly pyogenic Staphylococcus aureus and Streptococcus pneumonia

Question 17

Defects in C3 result in…

Answer 17

difficulty activating the complement system.

Question 18

Defects in C2 and C4, of the classical pathway, results in…

Answer 18

in an inability to clear immune complex and the development of systemic lupus erythematosus (SLE)

Question 19

Defects in the membrane attack complex (C5-C9) result in…

Answer 19

predisposition to severe infections with Neisseria meningitidis.

Question 20

Which complement system defects will result in an increased susceptibility to infections particularly pyogenic Staphylococcus aureus and Streptococcus pneumonia?

Answer 20

Defects in the mannan-binding lectin (MBL) and alternative pathway lead to an increased susceptibility to infections particularly pyogenic Staphylococcus aureus and Streptococcus pneumonia.

Question 21

Which complement system defects will result in difficulty activating the complement system?

Answer 21

Defects in C3 result in difficulty activating the complement system.

Question 22

Which complement system defects will result in an inability to clear immune complex and the development of systemic lupus erythematosus (SLE)?

Answer 22

Defects in C2 and C4, of the classical pathway, results in an inability to clear immune complex and the development of systemic lupus erythematosus (SLE).

Question 23

Which complement system defects will predispose to

severe infections with Neisseria meningitidis?

Answer 23

Defects in the membrane attack complex (C5-C9) predispose to severe infections with Neisseria meningitidis.

Question 24

How are immune deficiencies classified as primary or secondary?

Answer 24

Defects in immunity can be classified into primary disorders due to an intrinsic defect (genetic) in the immune system or secondary to a loss of previously functional immunity as a result of various disease states. Secondary immunodeficiency may be due to the disease process or the therapy used to treat a disease.

Question 25

Are primary or secondary immune deficiencies more common?

Answer 25

Secondary immunodeficiency is much more common than primary immunodeficiency

Question 26

Where is the most common site for infection to develop in immunodeficiency patients??

Answer 26

respiratory tract

Question 27

What immune defect is likely in the context of pneumocystis carini or CMV pneumonia?

Answer 27

T-cell defect (especially HIV)

Question 28

What immune defect is likely in the context of severe/atypical mycobacteria?

Answer 28

T-cell defect (especially HIV) or dendritic cells and monocytes

Question 29

What immune defect is likely in the context of candida and aspergillum pneumonia?

Answer 29

neutrophil or macrophage defect

Question 30

Causes of Secondary Immunodeficiency

Answer 30

Malnutrition
Corticosteroids
Chemotherapeutic Agents
Immunosuppressive Drugs in Transplantation
Immunosuppression in Autoimmune Diseases
Infections
HIV

Question 31

What is the most common cause of

depression of the immune system worldwide?

Answer 31

Malnutrition leading to severe protein deficiency

Question 32

What types of immune defects result from Malnutrition?

Answer 32

Malnourished individuals have impaired antibody production following immunization, defects in cell mediated immunity, impaired phagocyte function and decreased complement activity.

Protein losing enteropathies (Crohn’s, ulcerative colitis, or coeliac disease) can lead to loss of immunoglobulin through the gut, with similar humoral immunodeficiencies.

These defects are reversed by adequate protein and
calorific supplementation.

Question 33

Give an example of a Protein losing enteropathies

Answer 33

Protein losing enteropathies (Crohn’s, ulcerative colitis, or coeliac disease) can lead to loss of immunoglobulin through the gut, with similar humoral immunodeficiencies.

Question 34

What is Iatrogenic Secondary Immunodeficiency?

Answer 34

Iatrogenic secondary immunodeficiency results from medical treatment, particularly the use of chemotherapy in patients with cancer and deliberate immunosuppression for patients with an autoimmune disease or following organ transplantation.

Question 35

What group of drugs are used for the prevention

of graft rejection, treatment of autoimmune, allergic and malignant diseases?

Answer 35

corticosteroids

Question 36

List 2 ways that Corticosteroids lead to inhibition of Inflammation

Answer 36

􀁸 Inhibit nuclear factor kB (NF-kB) a transcription factor important in the transcription of many genes in both innate and adaptive immune responses.
􀁸 Down-regulate the expression of several genes that code for inflammatory cytokines.
􀁸 Reduce production of prostaglandins.
􀁸 Reduce activity of neutrophils and maturation of macrophages.
􀁸 Reduce proliferation of T cells.
􀁸 Decrease endothelial cell function.

Question 37

List 2 ways that Corticosteroids lead to inhibition of Wound Healing and Repair

Answer 37

􀁸 Decrease natural killer cell function (decrease in nitric oxidase synthase activity).
􀁸 Decrease antigen handling (decreased maturation of monocytes to macrophages).
􀁸 Inhibit expression of adhesion molecules causing inhibition of leukocyte migration to sites of inflammation inhibiting the activity of inflammatory cells.
􀁸 Reduce phagocytosis and killing by neutrophils and macrophages.

Question 38

List 2 ways that Corticosteroids lead to Change in Immune Cell Traffic

Answer 38

􀁸 Inhibit T-cell activation and T-cell function.
􀁸 Increase in neutrophils in the blood (released from bone marrow and failed exit to tissues).
􀁸 Decrease monocytes in blood.
􀁸 Decrease lymphocytes in blood (increased apoptosis of CD4+ cells).
􀁸 Cytotoxic T cells sequestered in bone marrow.

Question 39

Anti-metabolite chemotherapy agents act on which stage of the cell cycle?

Answer 39

S phase

Question 40

Alkylating chemotherapy agents act on which stage of the cell cycle?

Answer 40

G1

Question 41

Patients having anti-cancer treatment whose neutrophil count is 0.5×109 per litre or lower and who have either a temperature higher than 38 C or other signs or symptoms consistent with clinically significant sepsis are diagnosed with…

Answer 41

Neutropenic sepsis, a life-threatening complication of anti-cancer treatment.

Neutropenic sepsis is an acute medical emergency. Initial clinical assessment includes history and examination, full blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture.

Question 42

Neutropenic sepsis is an acute medical emergency. Initial clinical assessment includes…

Answer 42

history and examination, full blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture.

Question 43

Immunosuppressive drugs are used in combination to interfere with specific immune mechanisms to facilitate graft survival but allowing the immune system to function sufficiently to minimise the incidence of opportunistic infections.

Describe a mechanism by which these drugs work.

Answer 43

1. Cyclosporine and tacrolimus are two drugs that bind to intracellular proteins involved in lymphocyte signalling pathways. Binding blocks an intracellular signalling protein essential for transcription of the IL-2 gene. Thus, interfering with T-cell activation, cytokine production
   and clonal expansion of lymphocytes.
2. Cytotoxic drugs were developed to treat cancer. These drugs are also cytotoxic to lymphocytes and therefore used as immunosuppressive agents.
3. Immunosuppressive antibody preparations can be used as induction therapy begun at the time of the transplant and continue for about two weeks after transplantation to reduce immediate rejection of the graft e.g. Basilixmab.

Question 44

Patients who have had a splenectomy are susceptible to infections with organisms that share which feature

Answer 44

encapsulated

This is because splenic B lymphocytes are
important in the production of protective antibody IgG2 against pneumococcal cell wall and other carbohydrate antigens

All patients should receive immunization with pneumococcal conjugate vaccine, receive prophylactic penicillin and be vaccinated against Haemophilus influenza type b (Hib) and N meningitides.

Question 45

Patients who have had a splenectomy are susceptible to infections with encapsulated organisms. Why ?

Answer 45

This is because splenic B lymphocytes are important in the production of protective antibody IgG2 against
pneumococcal cell wall and other carbohydrate antigens.

All patients should receive immunization with pneumococcal conjugate vaccine, receive prophylactic penicillin and be vaccinated against Haemophilus influenza type b (Hib) and N meningitides.

Question 46

What cells are eliminated in HIV?

Answer 46

HIV associated disease is characterised by major defects in immunity following the elimination of CD4 cells.

The effect of HIV is the blunting of T lymphocyte mediated responses.

Question 47

HIV associated disease is characterised by major defects in immunity following the elimination of CD4 cells. What is the function of CD4 cells?

Answer 47

Normal CD4 cells play a key role in responding to antigen by releasing lymphokines, interferons and B cell
growth factors. These regulate growth, maturation and activation of cytotoxic T cells (anti-viral) macrophages (anti-intracellular bacteria, protozoa and fungi) and natural killer cells (involved in tumour surveillance).

Question 48

Are more or less virulent opportunist infections seen early in HIV progression?

Answer 48

As the immune system is destroyed, the more virulent opportunist infections (e.g. tuberculosis) develop earlier, and the less virulent (e.g. M. avium-intracellulare) later.

Early: Kaposi’s, TB, toxoplasmosis.

Late: Pneumocystis, CMV, mycobacteriosis

Question 49

A 37-year-old woman presented with a large, painless swelling in her neck. The enlargement had been a gradual process over 2 years. She has felt increasing tired, gained weight and developed dry itchy skin over the same time period. On examination, her thyroid was diffusively enlarged and had a rubbery consistency.

T3 was 0.6nmol.l-1 (NR 0.8-2.4),
T4 was 9nmol.l-1 (NR 9-23)
TSH was 6.3mU.l-1 (NR 0.4-5).

However, her serum contained high titre antibodies to thyroid peroxidase (1/64000; 4000 iu.ml-1).

Name the condition the woman is suffering from?

Answer 49

Hashimoto’s thyroiditis

Question 50

What is the difference between T4 and T3? Which is the active form of the thyroid hormones?

Answer 50

T4 has four iodine attached to the molecule, T3 has three. T3 is the active form.

Question 51

List the main steps in the synthesis of thyroid hormones

Answer 51

Iodination of tyrosine, incorporation into thyroglobulin, secretion of iodothyroglobulin into follicle, re-sequestration into cell, coupling of iodotyrosines, proteolysis, secretion of T4 into blood.

Question 52

Identify precisely the source of thyrotropin stimulating hormone (TSH) secretion in the body. How is TSH secretion normally controlled?

Answer 52

Thyrotrophs in the anterior pituitary. Normally stimulated by Thyrotrophin Releasing Hormone from the hypothalamus travelling in the hypophyseal portal circulation

Question 53

Where is the precise anatomical location of the thyroid gland?

Answer 53

On the anterior side of the neck, lying against and around the larynx and trachea, just below the laryngeal prominence, or ‘Adam’s Apple’.

Question 54

What is causing enlargement of the thyroid gland in Hashimoto’s?

Answer 54

In Hashimoto disease, enlargement of the thyroid gland occurs because of infiltration by lymphoid cells.

Question 55

What would be the gross appearance of a thyroid gland after a very long period of chronic inflammation?

Answer 55

Prolonged chronic inflammation causes destruction of follicles and replacement by scar tissue, causing the thyroid gland to shrink.

The replacement of normal thyroid gland parenchyma by a dense mononuclear infiltrate, including germinal centres. The remaining follicles often develop very eosinophilic cells, sometimes called Hurthle cells.

Question 56

When germinal centres are formed in the thyroid, what is the likely nature of the lymphoid infiltrate?

Answer 56

The presence of germinal centers indicates infiltration by B lymphocytes.

Question 57

What does the presence of germinal centres in the thyroid indicate?

Answer 57

The presence of germinal centres indicates that there is local production of an immune response, mainly involving B cells.

Question 58

Is Hashimoto thyroiditis cell mediated or antibody mediated?

Answer 58

Hashimoto thyroiditis is believed to be initiated by the development of autoreactive T cells, but B cells are also involved, and several autoantibodies develop.

Question 59

In Hashimoto thyroiditis, when the inflammation subsides, what replaces the damaged thyroid follicles?

Answer 59

Collagen replaces thyroid follicles.

Question 60

Do thyroid epithelial cells have the capacity to regenerate?

Answer 60

Yes, they can regenerate.

Question 61

Name the three classification of tissues based on their regenerative capacity, give an example of each

Answer 61

The three categories are labile cells, stable cells, and permanent cells. Labile cells (e.g., gut epithelium) are continuously dividing; stable cells (e.g., liver, thyroid epithelium, endothelium) are not dividing, but can enter the cell cycle; permanent cells (e.g., neurons) either cannot divide or can divide only very rarely.

Question 62

What does the presence of collagen indicate about the duration of an inflammatory process in the thyroid?

Answer 62

It indicates the presence of chronic inflammation, which caused tissue damage and subsequent repair.

Question 63

What factors determine whether a tissue damaged by inflammation is replaced by a scar or by normal cells of that tissue?

Answer 63

This is determined by two factors. The first is the type of cells (i.e., labile, stable, or permanent). The former two types can regenerate. The second factor is whether damage to the supporting framework has occurred. If the
supporting stroma collapses, even if cells can regenerate, the normal tissue architecture cannot be replaced; this occurs in cirrhosis of the liver.

Question 64

What is immunological tolerance? Why is it important?

Answer 64

The adaptive immune system does not normally mount effective immune responses to self-molecules. This state of immune unresponsiveness is called tolerance and is important because T and B cells expressing antigen receptors that may recognize self-antigens arise during lymphocyte development, and these lymphocytes must be controlled or eliminated to prevent autoimmune disease. Also, the mechanisms of tolerance induction may be exploited to inhibit harmful immune responses to allergens, self-antigens, and transplants.

Question 65

What possible mechanism by which infection can promote the development of autoimmunity?

Answer 65

Infections may promote the development of autoimmunity by (a) inducing co-stimulatory molecule expression by APCs that present self-antigens to lymphocytes; (b) causing inflammation and tissue damage, which exposes normally sequestered self-antigens to the immune system; and molecular mimicry, if the microbe expresses an antigen molecularly similar to a selfantigen, and thereby simulating an immune response (antibodies or T cells) that cross-reacts against self-antigens.

Question 66

What is central tolerance?

Answer 66

Central tolerance is the elimination or inactivation of self-reactive T and B cells during their development in the thymus or bone marrow, respectively.

Question 67

How is central tolerance induced in T lymphocytes?

Answer 67

Central tolerance is induced in immature T cells in the thymus after they express T cell receptors. If a developing T cell recognizes, with high avidity,
peptides derived from self-proteins bound to self MHC presented by thymic antigen-presenting cells, signals will be generated that lead to apoptosis of the T cell (called clonal deletion or negative selection). Surviving CD4+ T cells may develop into harmless and protective regulatory T cells.

Furthermore, some proteins mainly expressed by cells in a particular peripheral tissue type or organ may be also expressed by medullary thymic epithelial cells (MTECs)
under the control of the AIRE protein. The developing T cells that recognize peptides from these self-proteins in complex with self MHC are deleted.

Question 68

How is central tolerance induced in B lymphocytes?

Answer 68

Central tolerance develops in immature B cells after they express a functional membrane B cell receptor complex. Immature B cell recognition of self-antigens will lead to apoptosis or to receptor editing, whereby a new round of V-D-J recombination in the light-chain genes generates new specificities that are not self-reactive.

Question 69

Where do regulatory T cells develop, and how do they protect against autoimmunity?

Answer 69

Most regulatory T cells (Tregs) are CD4+ T cells that express the IL-2 receptor a chain CD25 and the transcription factor FoxP3.

Tregs develop in the thymus from immature thymocytes as a consequence of self antigen recognition. Tregs can also differentiate from mature naive T cells in peripheral lymphoid tissues as a result of antigen recognition together with signals from cytokines such as TGF-b.

Question 70

How do regulatory T cells protect against

autoimmunity?

Answer 70

Regulatory T cells protect against autoimmunity by suppressing activation of self-reactive T cells by antigen presenting cells (APCs) or by directly inhibiting the T cells. The mechanisms by which Tregs suppress APCs or T cells involve both direct cell-cell contact and secretion of cytokines (e.g., TGF-b, IL-10).

Question 71

How is functional anergy induced in T cells? How may this mechanism of tolerance fail to give rise to autoimmune disorders?

Answer 71

Anergy, a mechanism of peripheral tolerance, is a long-lasting condition in which a T cell will not respond to antigen stimulation. Anergy is induced in naive T cells when they recognize peptide–MHC antigen without
costimulation. The mechanisms of anergy include blocks in signalling downstream from the T cell receptor or the preferential engagement of inhibitory receptors. Anergy may also occur when “immature” dendritic cells, which have not been exposed to microbial stimuli, process and present self peptide-MHC to T cells. Such DCs will not express sufficient levels of B7- 1, B7-2, or other molecules to provide costimulation, and therefore the self-reactive T cell will become anergic. Anergy may fail during an infection when a T cell recognizes self peptide-MHC on a DC that has been activated by innate responses to the microbe.