10. Immunopathology: Immunodeficiency

Question 1

Understand features of immunodeficiency diseases

• Primary Immunodeficiencies:
• ________ determined
• Typical Clinical Presentation: __________
• 4 types:

Answer 1

• Primary Immunodeficiencies:
• Genetically determined
• Typical Clinical Presentation: infant with increased susceptibility to recurrent infections
• 4 types:
  1. Humoral Immunodeficiency
  2. Cellular Immunodeficiency
  3. Combined Immunodeficiency
  4. Nonspecific Immunodeficiency

Question 2

Primary Immunodeficiencies

What are the four Primary Immunodeficiencies?

Answer 2

1. Humoral Immunodeficiency
2. Cellular Immunodeficiency
3. Combined Immunodeficiency
4. Nonspecific Immunodeficiencyc

Question 3

1° & 2° immune deficiency syndromes:

Pathogenesis

For primary and secondary immune deficiency syndromes, understand
– Pathogenesis
– Immunological features
– Clinical presentation

Answer 3

pending

Question 4

What is humoral immunity?

Answer 4

Humoral immunity is also called antibody-mediated immunity. With assistance from helper T cells, B cells will differentiate into plasma B cells that can produce antibodies against a specific antigen. The humoral immune system deals with antigens from pathogens that are freely circulating, or outside the infected cells.

Question 5

Major difference between humoral and cell-mediated immunity?

Answer 5

The major difference between humoral and cell-mediated immunity is that humoral immunity produces antigen-specific antibodies, whereas cell-mediated immunity does not. T lymphocytes, on the other hand, kill infected cells by triggering apoptosis.

Question 6

What are Humoral Immune Deficiencies

Answer 6

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells.

Question 7

X-linked Aggamglobulinemia (Bruton’s Syndrome)
- Type of immonodeficiency?
- Characterized by?
- Defective Gene?

Answer 7

• inherited immunodeficiency (1° Humoral) disorder. It is
• characterized by the absence of mature B cells (therefore absence of antibodies) which in turn leads to severe antibody deficiency and recurrent infections
• ## Defective Gene: BTK on X-chromosome

agammaglobulinemia = “there are no gamma globulins in the blood”

Question 8

Clinical Features of Bruton’s Syndrome (Brutons Aggamglobulinemia)
Screening Test?

Answer 8

• distinctive clinical features
• early onset bacterial infections,
• absent mature B cells or
• remarkably reduced circulating B cells,
• severe reduction in the basal serum immunoglobulins,
• inability to produce antibodies against antigens, and
• occurrence of autoimmune diseases paradoxically
• The diagnosis of agammaglobulinemia should be coonsidered with: recurrent or severe bacterial infections, particularly if they have small or absent tonsils and lymph nodes. The first screening test should be an evaluation of serum immunoglobulins.

Question 9

IgA Deficiency
- Type of immonodeficiency?
- Characterized by?

Answer 9

• Most common immunodeficiency (1° Humoral)
• Defect in B-cell differentiation to IgA producing plasma cell
• an immune system condition in which you lack immunoglobulin A (IgA), a protein that fights infection (antibody)
• IgA is found in mucous membranes, mainly in the respiratory and digestive tracts. It is also found saliva, tears, and breastmilk. A deficiency seems to play a part in asthma and allergies. Researchers have also linked IgA deficiency to autoimmune health problems.

Question 10

Hyper-IgM Syndrome
- Type of immonodeficiency?
- Characterized by?
- Immunological Features
- Clinical Features

Answer 10

• 1° Humoral Deficiency
• Defect in T-B cell interaction -| Ig isotype switching
• Majority x-linked
• The affected protein is called CD40 ligand because it binds, or ligates, to a protein on B-lymphocytes called CD40. CD40 ligand is made by a gene on the X-chromosome
• Immunological features
• The disease is characterized by decreased immunoglobulin G (IgG) in the blood and normal or elevated levels of IgM.
• Clinical Features:
• Most patients with HIGM syndrome develop clinical symptoms during their first or second year of life. The most common problem in all forms of HIGM syndrome is an increased susceptibility to infection including recurrent upper and lower respiratory tract infections. The most frequent serious infective agents are bacteria, but viral illnesses are also more frequent and severe.

Question 11

What are cellular immunodeficiencies?

Cellular immunity deficiencies (____ defects)(5 to 10% of primary immunodeficiencies)
- predispose to infection by ________, ____, ____, etc, and many common ______
- T-cell disorders also cause ____ deficiencies because the B- and T-cell immune systems are ________.

The most common T-cell disorders are:

• ____________
• ____________
• ____________
• ____________

Answer 11

Cellular immunity deficiencies (T-cell defects) account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, Pneumocystis jirovecii, fungi, other opportunistic organisms, and many common pathogens
- T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent.

The most common T-cell disorders are

• Chronic mucocutaneous candidiasis
• DiGeorge syndrome
• X-linked lymphoproliferative syndrome
• Zeta-associated protein 70 (ZAP-70) deficiency

Question 12

DiGeorge Syndrome

• ____ defect of the __________
• _________________
  Immunological features
• ________
  Clinical features:
• ________

Answer 12

DiGeorge Syndrome
- Embriogenesis defect of the 3rd and 4th pharyngeal pouches
* Thymic hypoplasia
* DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia
* Immunological features
- T cells (T lymphocytes) are major components of the adaptive immune system. Their roles include directly killing infected host cells, activating other immune cells, producing cytokines and regulating the immune response.
* Clinical features:
- low-set ears,
- midline facial clefts,
- a small receding mandible,
- hypertelorism,
- a shortened philtrum,
- developmental delay,
- congenital heart disorders
- Thymic and parathyroid hypoplasia or aplasia, causing T-cell deficiency and hypoparathyroidism.

Thymus - “school house” where T-cells are educated

Question 13

Describe the two types of Bare Lymphocyte Syndrome

Answer 13

Type 1: Decreased MHC I
- Rare, autosomal recessive defect of TAP genes
- CD8+ T-cell
Type 2: Decreased MHC II
- Defective transcription factors
- **CD4+ T-cell **

Cellular Immunity Deficiciency

Question 14

What is combined Immunodeficiency (SCID)

Answer 14

Third type of 1° Immunodeficiency
- Constellation of genetic syndromes
- Inheritance:
- Defects of both humoral and cellular immunity
Immunological Features
Clinical Presentation
- low to absent T cells
- low, high, or normal number of B cells and natural killer cells.
- Most infants develop opportunistic infections within the first 3 months of life.
- Diagnosis is by detecting lymphopenia, absence or a very low number of T cells, and impaired lymphocyte proliferative responses to mitogens.
- Patients must be kept in a protected environment; definitive treatment is hematopoietic stem cell transplantation.

Question 15

What is the Fourth type of 1° Immunodeficiency, Nonspecific Immunodeficiency: Phagocytes
Chronic Granulomatous vs Chdiak Higashi syndrome

Answer 15

• genetic disease
• phagocytes do not make hydrogen peroxide and other chemicals needed to kill certain bacteria and molds (Chronic Granulomatous Diseases
• Chediak Higashi Syndrome:Giant lysosomal granules develop in neutrophils and other cells (eg, melanocytes, neural Schwann cells). The abnormal lysosomes cannot fuse with phagosomes, so ingested bacteria cannot be lysed normally.
• patients get more infections, and they also get too many immune cells forming “knots” called granulomas, hence the name of the disease.

Question 16

What causes Secondary Immunodeficiency?

Answer 16

caused by external factors or diseases
- Immunoglobulin loss
- Neoplasia
- Aging
- Malnutrition
- Iatrogenic Immunosuppression
- Infectious disease
- (Acquired Immunodeficiency Syndrome)
- AIDS

Question 17

AIDS Immunopathology

Answer 17

• Lymphopenia
• Decreased T-cell function
• Altered Macrophage Function
• Altered B-cell activation