Immunodeficiencies

Martin Liška

Basic immunological termsImmune system provides 3 basic functions:a) Defense against infectionb) Homeostasis – elimination of old or impaired cellsc) Immunological surveillance - elimination of mutated cells

Endocrine system

Immune system Nervous system

Disorders – detectable by laboratory or histological methods, without clinical manifestationClinical manifestation – decreased function - immunodeficiencies - increased function – allergy, autoimmunity

Immunodeficiencies

• Humoral – innate immunity - complement, MBL acquired immunity – immunoglobulins (B lymphocytes)

• Cell mediated immunity – innate immunity – phagocytes - acquired immunity – T lymphocytes

• Primary – congenital, genetically defined, symptoms predominantly at an early age

• Secondary – the onset of symptoms at any age chronic diseases the effects of irradiation immunosuppression surgery, injuries stress

Immunodeficiencies – critical life periods in respect to symptoms onset

• Newborn age - severe primary disorders of cell mediated immunity

• 6 mth. – 2 yrs. – severe humoral immunodeficiencies cong./transient

• 3 - 5 yrs. – transient and selective humoral immunodeficiencies, secondary immunodeficiencies

• 15 – 20 yrs. – hormonal instability, thymus involution, life-style changes, some typical infections first symptoms of CVID

• Middleage – often excessive workload, stress first symptoms of autoimmune disorders (also immunodeficiency)

• Advanced and old age – rather symptoms of severe secondary immunodeficiencies,

repercussion of functional disorders

Immunodeficiencies – major clinical features

• Antibodies - microbial infections (encapsulated bacterias) respiratory - pneumonia, sinusitis, otitis

GIT – diarrhea• Complement – microbial infections (pyogenic), sepsis various systems affection edema (HAE) – C1-INH deficiency• T lymphocytes - bacterial, fungal, viral GIT – diarrhoea respiratory – pneumonia, sinusitis• Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammations

The differentiation of pluripotent stem-cell

I. Primary immunodeficiencies – phagocytic cell defects

1/ Quantitative – decreased numbers of granulocytes –neutrophil elastase mutation

Congenital chronic agranulocytosis

Cyclic agranulocytosis (neutropenia)• Systemic manifestation, fevers in 3-weeks cycles in

cyclic form• Treatment with granulocyte growth factors, ATB

I. Primary immunodeficiencies – phagocytic cell defects2/ Qualitative – phagocytes functional disorders, various enzyme

deficits, inability of phagocytes to degrade the ingested material

Chronic Granulomatous Disease (CGD)• Approximately in 60% X-linked • Enzymatic inability to generate toxic oxygen metabolites (H2O2)

during oxygen consumption) - result of defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase)

• Inability to kill bacteria such as Staph.aureus, Pseud.aeruginosa that produce the enzyme catalase

• Clinical features: granulomas in many organs• Treatment: long-term ATB administration

• Myeloperoxidase deficiency• Recurrent microbial infections, susceptibility to Candida albicans and

Staph.aureus infections

I. Primary immunodeficiencies – phagocytic cell defects

Chédiak-Higashi syndrome• Clinical features: recurrent, severe, pyogenic infections

(streptococcal, staphylococcal)• Defective intracellular killing of bacteria (neutrophils

contain abnormal giant lysosomesLAD syndrome – Leukocyte Adhesion Deficiency (neutrophil

adhesion molecules deficiency)• LAD I – integrins expression deficiency• LAD II – selectins expression deficiency

II. Primary immunodeficiencies – B cell disorders

Bruton’s X-linked hypogamaglobulinemia• Blockage in the maturation of pre-B lymphocytes into B lymphocytes

(tyrosine kinase defect)• Frequency 1: 50-100 thousands• Undetectable or very low serum levels of Ig• Clinical symptoms in 5-9 mth.of age• Pneumonia, pyogenic otitis, complicated sinusitis, increased occurrence

of pulmonary fibrosis• Treatment: life-long IVIG or subcutaneous substitution with Ig

CVID – Common Variable ImmunoDeficiency• B cell functional disorder, mostly low levels of IgG and IgA• Frequency 1:100-200 thousands. Symptoms’ onset between 2nd and 3rd

decade• Recurrent respiratory tract infections (pneumonia)• Treatment: IVIG substitution

II. Primary immunodeficiencies – B cell disorders Selective IgA deficiency• Disorder of B cell function • Frequency 1: 500-700, manifestation mostly at pre-school age• Recurrent mild/moderate infections (respiratory, GIT, urinary tract)

or asymptomatic• Risk of reaction to live attenuated vaccines or generation of anti-IgA

antibodies after a blood transfusion• Laboratory criterion: IgA < 0,07g/l (age > 4 years)

Selective IgG subclasses or specific IgG deficiency • B cell function disorder• Frequency ?• Onset of symptoms in childhood, mostly respiratory tract infections

caused by encapsulated bacteria (H.influenzae, Pneumococci) Transient hypogammaglobulinemia of infancy

III. Primary immunodeficiencies – T cell disorders

diGeorge syndrome• Disorder of prethymocytes maturation due to absence of thymus• Disorder of development of 3rd and 4th branchial pouch – absence of

parathyroid glands • Congenital heart diseases• Frequency 1 : 100 thousands• The onset of symptoms after the birth – hypocalcemic spasms and

manifestations of cong.heart disease• Immunodeficiency could be only mild, the numbers of T lymphocytes

later usually become normal• Treatment symptomaticHyperIgE (Job’s) syndrome• Most frequently mutation of STAT3 gene (↓ Th17)• Recurrent “cold” staphylococcal abscesses, chronic eczema, otitis

media• Extremely high serum IgE levels• Treatment: ATB

III. Primary immunodeficiencies – T cell disorders

Lymphoproliferative syndrome• Malignant proliferation of activated T lymphocytes• Hypogamaglobulinaemia, lymphoma• Its development is induced by EBV infectionChronic mucocutaneous candidiasis• Impaired ability of T cells to produce macrophage migration inhibiting

factor (MIF) in response to Candida antigenBare lymphocyte sy. • Disorder of antigen presentation – defect of MHC I and/or MHC II

expression leads to the dysfunction of CD4 and CD8 lymphocytesIFN-g Receptor deficiency • Th1 lymphocytes differentiation disorder inability of intracellular killing of Mycobacteria (fatal BCG itis)

DiGeorge sy

MHC I, MHC II def. (bare lymphocyte sy), CD3 def.

IV. Primary immunodeficiencies – combined defects of T and B cells

• SCID – Severe Combined ImmunoDeficiency• X-linked recessive or AR disease, combined disorder of humoral and cell mediated

immunity• Severe disorder (patients often die during first 2 years of life), symptoms’ onset soon

after the birth (severe diarrhoea, pneumonia, meningitis, BCGitis)• Immunological features: typically lymphopenia and thymus hypoplasia• Forms: AR form – often enzymatic deficiency (ADA, PNP) that leads to accumulation of metabolites toxic to DNA synthesis (lymphocytes) X-linked form – disorder of stem-cell Treatment: ATB, IVIG BMT is of critical significance in ADA deficiency the gene therapy was tested successfully

• Reticular dysgenesis• Stem-cell differentiation is blocked• Very rare• Symptoms immediately after the birth – severe diarrhoea, infections of deep layers• Fatal, BMT is the only treatment

SCID

Reticular dysgenessis

IV. Primary immunodeficiencies – combined defects of T and B cells

Ataxia teleangiectasia • Increased radiation induced chromosomal breakage, ataxia,

dilatation of small blood vessels (teleangiectasia)• Neurological disorders, immunodeficiency is not necessary (if

present, IgA deficiency or T lymphocytes function disorders are most common)

• Treatment: ATB, IVIG

Hyper IgM syndrome • CD40L expression disorder, poor cooperation of B and T cells,

impaired isotype switching, increased IgM levels

Wiskott-Aldrich syndrome • thrombocytopenia, eczema, recurrent infections (encapsulated

microbes), decreased IgM levels

ADA, WAS PNP, A-T sy

Adenosin deaminase ADA , Purin nucleosid phosphorylase PNPWiscott-Aldrich syndrome WAS Ataxia-teleangiectasia sy A-T

V. Primary immunodeficiencies – complement system disorders

Deficiency of:• C1, C2, C3, C4 – impaired opsonization, susceptibility to

infections, autoimunity, SLE–like syndrome• C6, C7, C8, C9 – SLE–like syndrome, increased

susceptibility to neisserial infections• MBL deficiency – mannan binding lectin (lectin way of

complement activation), various infections, susceptibility to autoimmunity, association with allergy.

V. Primary immunodeficiencies – complement system disorders

Hereditary angioedema (HAE)

• Absence or functional deficiency of C1-inhibitor• Skin and/or mucosal (oral, laryngeal, gut) edemas caused by

overproduction of bradykinin (regulated by C1-inhibitor)• Injuries or surgical/stomatological operations are mostly the

triggering factor • Laryngeal edemas could be life-threatening, immediate treatment is

necessary !• Treatment: preventive – androgens, EACA immediate – C1-INH concentrate or fresh frozen plasma administration, icatibant (selective bradykinin receptor inhibitor)• Secondary form also exists !

Secondary immunodeficiencies

• Acute and chronic viral infections – infectious mononucleosis, influenza

• Metabolic disorders – diabetes mellitus, uremia• Autoimmune diseases – autoantibodies against

immunocompetent cells (neutrophils, lymphocytes); autoimmune phenomena also after administration of certain drugs (e.g. oxacilin, quinidine)

• Allergic diseases• Chronic GIT diseases• Malignant diseases (leukemia)• Hypersplenism/asplenia• Burn, postoperative status, injuries• Severe nutritional disorders• Chronic infections• Ionizing radiation• Drug induced immunodeficiencies (chemotherapy)• Immunosupression• Chronic stress• Chronic exposure to harmful chemical substances

Secondary immunodeficiencies• Splenectomy – deficiency in generation of antibodies against

encapsulated microorganisms (Pneumococci, Neisseria)

• A loss of immunoglobulins – nephrotic syndrome - lymphangiectasies• Lymphomas, myelomas, CLL

Secondary immunodeficiencies - A.I.D.S.

• Caused by retrovirus HIV 1 or HIV 2• Current incidence 40 mil.people, predominantly in central Africa,

5mil. of new infections per year, 3 mil. deaths per year • CZ:10/06 - HIV+ 904/248, AIDS 204/14, deaths 23/2 • Virus has a tropism for cells bearing CD4 surface marker (Th CD4+

lymphocytes); also affects macrophages and CNS cells• Viral genome transcribes into human DNA and infected cell provides

viral replication• Transmission: sexual intercourse contact with blood endouterine (mother – fetus, breast milk)• Phases: acute (flu-like sy) asymptomatic – several years, viral replication symptomatic – infections, autoimmunity, malignancy,

allergy final – systemic breakdown, opportune infections

A.I.D.S. - Treatment

• Reverse transcriptase inhibitors (zidovudine, dideoxyinosine, dideoxycytosine, 3-thiacytosine)

• Protease inhibitors - block the viral protease enzyme• Combined drug therapy• Antimicrobial agents

Substitution therapy with immunoglobulins

• Prepared by fractionation of pooled human plasma from huge amount of donors (1000)

• Examination of donors, inactivating procedures to minimize the risk of infection transmission

• Mainly IgG, minimal content of IgA• i.v. (Octagam, Gammagard) or s.c. use (Subcuvia, Gammanorm)

Indications

• Primary humoral immunodeficiencies

• IgG subclasses deficiencies, deficiencies of generation of specific antibodies, secondary humoral immunodeficiencies, combined immunodeficiencies

Dosage

• agamaglobulinemia – IVIG 400-600 mg/kg/month• regular substitution in outpatient’s room every 3-4 weeks• „home therapy“ (s.c.administration by infusion pump)

Adverse effects

• Allergic reactions, or even anaphylaxis [in minor reactions (chill, headache) only slowing down of infusion is usually needed]