PRIMARY (INBORN) AND SECONDARY (ACQUIRED) IMMUNODEFICIENCIES (ID)

LECTURE 12

Jan Żeromski

2007/2008

PRIMARY ID: GENERAL DATA

• Relatively infrequent (average 1 per 100.000)

• Lack or improper function of one or more elements of immune system

• Increased susceptibility for infections but other follow ups include autoimmunity, hypersensitivity and malignancy

• Are hereditary, with familiar trait, often linked to X chromosome

PRIMARY IDs (ACCORDING TO WHO-1999)

• Combined

• Other well characterized

• Syndromes of chromosomal instability

• Appear with other inborn defects

• Other

• Disturbances of antibody biosynthesis

• Defects of fagocytosis

• Deficits of complement components

• Co-existing with defects of lymphoproliferation

SEVERE COMBINED IMMUNODEFICIENCY (SCID)DISEASE MECHANISM

1. Severe (T-B-SCID) Reticular dysgenesis Deficiency-RAG1,RAG2

Defects of stem cells and genes for Ig and TCR (recombinations)

2. Defective purine metabolism deficiency of ADA and PNP

Toxic metabolites for lymphocytes

3. Lack of expression of MHC antigens, class I and/or class II

Lack of gene transcription for MHC and TAP proteins

4. Hyper IgM syndrome Lack of CD40L signal from T to B cell

5. CD3 deficiency Defect of CD3-TCR proteins

6. Omenn syndrome (SCID with hypereosinophilia)

RAG1 and RAG2 mutations

COMBINED SCID

Disease• Severe (T-B-SCID)Reticular dysgenesis Deficiency-RAG1,RAG2• Defective purine

metabolism deficiency of ADA and PNP

• Lack of expression of MHC antigens, class I and/or class II

Mechanism• Defects of stem cells

and genes for Ig and TCR (recombinations)

• Toxic metabolites for lymphocytes

• Lack of gene transcription for MHC and TAP proteins

COMBINED SCID-contd.

Disease• Hyper IgM

syndrome

• CD3 deficiency• Omenn syndrome

(SCID with hypereosinophilia)

Mechanism• Lack of CD40L

signal from T to B cell

• Defect of CD3-TCR proteins

• RAG1 and RAG2 mutations

B CELL DEFICIENCIES

• X-linked agammaglobulinemia (Bruton disease) – lack of Btk kinase necessary for B cell formation;

• Common variable ID(CVID) – defects of T lymphocyte signaling to B cell;

• IgA deficiency defect of Ig class switch;

• Selective Ig subclass deficiency;

• Transient hypogammaglobulinemia of infants – maturation defect of Th cell function.

OTHER WELL CHARACTERIZED SYNDROMES OF ID

1. Wiskott-Aldrich syndrome (WAS)

mutation of Xp11.22 gene encoding WASP protein results in defects of cytoskeleton

of T cells (faulty collaboration among T and B cells)

Symptoms: thrombocytopenia, eczema,

infections, variations in Ig levels, risk of lymphoma

OTHER WELL CHARACTERIZED SYNDROMES OF ID (cont.)

2. DiGeorge syndrome (DGS)

congenital defect in the organs derived from

third and fourth pharyngeal pouches

(lack of thymus and parathyroids, malformations

of the heart and/or aortic arch)

Symptoms: viral and fungal infections,

neonatal tetany, distinctive facial features

SYNDROMES OF CHROMOSOMAL INSTABILITY

1. Hereditary ataxia-teleangiectasia (AT) lack of ATM kinase involved in repair of double-

strand breaks of DNA; defects of cell cycle control

Symptoms: as in the name, severe sinus and lung infections, T cell and B cell deficiencies

2. Nijmegen breakage syndrome (NBS) defects of rearrangement of Ig genes,

faulty DNA reparation (mutation of NBS1 gene)Symptoms: microcephaly, developm. retardation, Ig

deficiencies,T cell-lymphocytopenia

HEREDITARY PHAGOCYTE FUNCTION DEFICIENCIES

1. Chronic granulomatous disease (CGD)

comprises a group of 4 disorders with a common phenotype. Deficient superoxide (0-

2) generation via the phagocyte NADPH oxidase

Symptoms: recurrent infections, abscesses, granuloma formation

2. Chediak-Higashi syndrome

defect of lysosome formation; mutation of CHS1 gene

Symptoms: albinism, infections, photophobia, pancytopenia, lack of NK cell activity

DISORDERS OF PHAGOCYTE NUMBER

1.Kostman syndrome infantile agranulocytosis

Symptoms: severe infections, sepsis already at the newborn period

2.Cyclic neutropenia periodic (every 2-3 weeks) fall of neutrophil

number

3.Shwachman syndrome neutropenia, defects of chemotaxis and bacterial

killing

4.Chronic mild familiar neutropenia

HEREDITARY LEUKOCYTE FUNCTION DEFICIENCIES

Leukocyte adhesion deficiency (LAD)LAD1

defect of CD11/CD18 integrin chain (CD18) biosynthesis.

Symptoms: recurrent necrotizing infections, failure to form pus

LAD2defect of sialyl Lewis (CD15s) ligand for

the selectin family. Symptoms: growth and mental retardation, hypotonia, seizures, persistent periodontitis

Leukocyte adhesion deficiency (LAD-1)

• Is due to integrin gene defects – deficiency of CD18, forming 3 important molecules: CD18/CD11a (LFA-1), CD18/CD11b (Mac-1 or CR3, and CD18/CD11c (CR4 or p150,95)

• These molecules are expressed on different classes of leukocytes and mediate their adhesion to endothelium

Leukocyte adhesion deficiency (LAD-1) - 2

• Leukocytes show defective chemotaxis and adherence,

• T lymphocytes and NK cells have impaired cytotoxic activity,

• Infants show delayed umbilical cord separation, persistent leukocytosis, destructive peridontitis, recurrent infections (S. aureus, Pseudomonas, Klebsiella)

LAD type 2

• Leukocytes cannot roll on endothelial surface

• Rolling is due to selectins, which react with glycoproteins containing fucosylated shugars

• Genetic defect in conversion of mannose to fucose results in failure of normal synthesis of these selectin ligands, such as blood group sialyl Lewisx

• Sialyl Lewisx is defective (hypofucosylated)

LAD type 2 - 2

• Leukocytes cannot roll, so their export from vessel lumen is considerably retarded

• Clinical features: growth and mental retardation,strabismus, dysmorphia, persistent peridontitis

• Leukocytosis in absence of infection• Wound healing is not impaired

DEFICIENCIES OF COMPLEMENT COMPONENTS – 1% of ID

1. Deficits of classical pathway of activation

2. Deficits of C3 and of proteins of alternative pathway

3. Deficits of components of lectin pathway

4. Deficits of membrane attack complex (MAC) C5 –C9

5. Deficits of C1 inhibitor

OTHER PRIMARY ID

1. Job syndrome (hyper IgE):- faulty chemotaxis, high IgESymptoms: recurrent infections, severe eczema, facial and skeletal abnormalities, eosinophilia

1. Duncan disease: - X-linked lympho-proliferative syndrome

2. Failure of tubercle bacilli killing:- defect of IFN-R and /or IL-12R

3. Chronic muco-cutaneous candidiasis4. T CD4+ cell lymphopenia

TEN WARNING SYMPTOMS OF ID

1. Six or more infections per year

2. Two or more severe sinusitis per year

3. Antibiotic treatment lasting 2 months or longer without visible effect

4. Two or more pneumonias per year

5. Retardation of growth and development of child

TEN WARNING SYMPTOMS OF ID (CONTINUED)

6. Recurrent deep skin or organ abscesses

7. Persistent mycosis of oral cavity and skin in a child >1 year old

8. Necessity of long lasting application of intravenous antibiotics to control infection

9. Two or more severe infections such as encephalitis, osteitis, dermatitis, myositis, sepsis

10.Family history indicating primary ID

SECONDARY ID - CAUSES

1. Glycocorticoids: lympho- and monocytopenia, inhibition of T cell activation, IL-1 and TNF synthesis;

2. Cytostatics:act mainly on DNA and its synthesis;

3. Malnutrition;4. Deficits of elements (selene, magnesium,

iron etc.);5. Deficits of vitamins (A, C, D, B6, folic acid);6. AIDS;7. Other viral infections (mainly of herpes

group).

ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) – GENERAL DATA

• Etiology: HiV-1 and HIV-2 retrovirus (RNA)• M-tropic and T-tropic viruses (the latter

worse)• T-tropic form syncytia from infected and

non-infected cells, what results in rapid cell destruction

• HIV receptors: CD4 and chemokine receptors (CCR5, CCR3, CXCR4)

• Main reservoir of virus – lymphatic tissue

AIDS PATHOGENESIS

• Early period: fall of CD4+ cells, viremia, lack of immune response;

• Fall of viremia, an increase of TCD8+ cell number able to kill infected cells;

• Appearance of anti-HIV antibodies;• Growth of virus mutagenicity;• Dysfunction and decline of Th1 CD4+ cell

number with parallel increase of Th2 cells;• Development of symptomatic AIDS.

THANK YOU GOOD LUCK