Lecture

Immunodeficiencies

Definition

Immunodeficiency

The inability of the body to produce a sufficientimmune response. 

Primary and SecondaryImmunodeficiencies

Primary deficiencies – inherited: - inherited dysfunction of genes encoding molecules important for correct immune functioning.

Secondary deficiencies – acquired:- acquired damage of molecules and/or cells important for correct immune functions caused by external or internal factors

Deficiencies involve: - cellular and humoral immunity - Ag specific or non-specific mechanisms

Primary immune deficiences

1) Frequency: more frequent in men

2) Genetics: - point mutations, gene deletions- linked with X chromosome

3) Consequences- absence or dysfunction of a given molecule

Clinical manifestations

Clinical manifestations of immune deficiencies:

1) Increased susceptibility to infections

2) Autoimmune diseases

3) Lymphoproliferative diseases

4) Allergy

5) Without manifestations – replaced by other immune mechanisms or manifested only under certain conditions

Deficiences of innate immunity

Deficiencies of Innate Immunity

Deficiencies of innate immunity involve:

- phagocytosis

- complement

- combined immunodeficiencies

Frequency: frequent, serious medicinal problem

Deficiences in Complement

Deficiences are rare.

1) Deficiency in C1, C2, C3 and C4 - immune complexes - diseases like Lupus erythematodes- pyogenic infections

2) Defeciency of C1 inhibitor (hereditary angioedema)

Deficiences in phagocytosis

Number of phagocytes

1. Kostmann syndrome

2. Cyclic neutropenia

3. Reticular dysgenesis

Deficiences in phagocytosis

Function of phagocytes

1. Chronic granulomatous disease (CGD)defects in NADPH-oxidase, X linked

2. Leukocyte adhesion deficiency (LAD I, II)LAD I > defect in CD18 molecule – diapedesis, without manifestationsLAD II > defect in ligands for selectins (sialyl-Lex antigen)

3. Reticular Dysgenesis

Deficiences of acquired immunity

Deficiencies of Specific Immunity

Deficiences of specific immunity involve:

- deficiencies of antibody production

- T cell dysfunction

- combined immunodeficiencies.

Antibody deficiencies I

- Failure of B cells and Ab production.- Patients suffer from encapsulated microbes.

1) Agammaglobulinemia linked with X chromosome (Bruton)- Mutation in protein kinase C (Btk) encoding signal transduction through BCR- B cells and Ab of all classes totally absent in blood.

2) Selective immunoglobulin deficiencies (dysimmunoglobulinemia)

- Partial or total absence of some isotypes - The most frequent is IgA deficiency. In mucosa, partially supplied by IgM,

in lower respiratory by IgG.- Without manifestations or higher sensitivity to respiratory infections, allergy, autoimmunity (and tumors?)

Antibody deficiencies II

3) Selective deficiency of IgG subclasses

Deficiency of IgG subclasses also in combination with IgA deficiency

4) Selective deficiency of Ab specific for certain AgDeficiency of Ab against lipopolysaccharides

5) Transient hypogammaglobulinemia of infancyDelayed onset of IgG production in newborns. Spontaneous recovery.

Common variable immunodeficiency( CVID )

Definition

Mixed group of diseases in which the production of antibodies is defective.Increased risk of life-threatening infections.

COURSE

Clinically, CVID may resemble HIV infection, as it may cause

• weight loss• swelling of the lymph nodes• diarrhea• lymphoma• idiopathic thrombocytopenic purpura

CVID

CVID

Symptoms :

INFECTIONS• Acute, recurring bacterial infections, including pneumonia, bronchitis and sinusitis.

• infections from Hemophilus spp. , Streptococcus pneumoniae , herpes, GI-tract infections

• Children with CVID are susceptible to otitis media, and infections may develop in the joints, bones, skin and parotid glands.

AUTOIMMUNITY• Autoimmune diseases (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis, celiac disease)

CANCER increased risk cancer (non-Hodgkin lymphomas and adenocarcinomas)

•Aethilogy

• homozygous null mutations in ICOS gene => panhypogammaglobulinemia

• a susceptibility locus exists in the class III MHC region

• Cause of CVID is uncertain and may vary among patients.

• in 10% of cases familiarity exists

CVID

Pathogenesis:

• Many patients with CVID have near-normal numbers of antibody- bearing B cells, but these fail to mature into plasma B cells -> low IgG, IgA and IgM (or undetectable amounts of the immunoglobu- lins).

• Other CVID patients have low numbers of B cells.

• Some have abnormalities of T-cells (ICOS gene).

CVID

CVID

Epidemiology:

• CVID is the most common clinically significant primary immunodeficiency disease (several thousand patients)

• It occurs equally in both sexes.

• CVID may become apparent in infancy or as late as the 5th decade of life. The average age of onset is 27 years.

CVID

Treatment

- prophylactic administration of human immunoglobulin every 3 weeks throughout the patient's life, along with

- systemic antibiotics as necessary for the management of concomitant infections.

T cell immunodeficiences

Distinguished as:

• severe combined disorders - T cell totally absent

• diseases caused by functionally abnormal T cells

T cell immunodeficiences

Severe combined immunodeficiency

- The most serious primary deficiency- Manifested early after delivery – viral infections, intracellular microbes, opportunistic microbes- Lethal without treatment

- Aethiology: heterogeneous, increasing number of diseases

T cell immunodeficiences

1. Adenosin deaminase deficiency

2. Severe Combined Immunodeficiency (SCID)

3. Reticular dysgenesis

Combined immunodeficiences

1. Ag presentation 6. Omen Syndrome

2. Activation of T cells 7. Hemophagocytic Lymphohistiocytosis

3. Hyper IgM syndrome 8. X-linked Lymphoproliferative Syndrome

4. Wiscott-Aldrich syndrome 9. Familiar Autoimmune Lymphoproliferative

Syndrome 5. Chediak – Higashi syndrome

Other Deficiences

Hyperimmunogamaglobulinemia (Job syndrome)

Mucocutaneous candidosis

Ataxia teleangiectasia

Secondary Immunodeficiences

Deficiences are caused by

1) Infections (HIV)

2) Metabolic disease (diabetes melitus, kidney and liver dysfunctions

3) Nutrition (proteins, vitamins, minerals)

4) Treatment procedures (splenectomy, chemotherapy...)

Autoimmunity

Immunopatologic reactions

Immune mechanisms recognize self antigens and destructself cells and molecules

Autoimmunity

Mechanisms (intrinsic factors):

1.) Association with certain MHC molecules >>> HLA-B27 -Bechterev disease

2) Deficiency in cytokines

3) Deficiency in genes which regulate apoptosis (Fas, FasL, Bcl-2)

4) Association with immunodeficiencies

5) Polymorphism of TCR genes and H chains of Immunoglobulines

6) Hormonal effects

Autoimmunity

Mechanisms (external factors):

Infections, stress, drugs, UV radiation

1) Cryptic Ag (intracellular)

2) expression of MHCII - inflammatory cytokines – presentation of Ag, which are normally not accessible

3) :”Molecular mimicry” similarity of self and microbial antigens

4) Microbial superantigenes

Autoimmunity

Mechanisms (external factors):

Infections, stress, drugs, UV radiation

1) Cryptic Ag (intracellular)

2) expression of MHCII - inflammatory cytokines – presentation of Ag, which are normally not accessible

3) :”Molecular mimicry” similarity of self and microbial antigens

4) Microbial superantigenes

Autoimmunity

Lupus erytematodes

Reumatoid artritis

Sjörgen disease

Systemic sclerodermitis

Connective tissue disease

Antiphospholipid disease

Vasculitis

Autoimmunity

Hashimoto thyroiditis

Graves-Basedow disease (TSH)

Diabetes melitus

Myasthenia gravis (acetylcholine receptors)

Hematological (cytopenias)

Skin autoimmune reactions