Environment

self

Non-self

Dangerous

Pathogenic

Immune system

Tolerance

Immune response

The immune system is still the big black box

BactBacteriaeria

ViVirusesruses

parasitesparasites

VViirusrus

3 3 hrshrs

3 3 hrhrss

DiversityFast development

PATOGENS

PATHOGENS HAVE SHORT GENERATION TIME

Humans have longer generation time, Need a sophysticated protection system

Development, education

Birth

Reproducrionat 35

IMMUNODEFICIENCIESAGE AND HEALTH DEPENDENTIMMUNOSUPPRESSIVE DRUGS

• INHERITED (PRIMARY)– Loss of function mutation

of genes of the immune system

– Enhanced susceptibility to infections

– Particular types of pathogens depending on the gene defect

– Did not show up until 1950 - antibiotics

• ACQUIRED– Due to infectious

diseases – AIDS– Other virus infections– Malnutrition– Artificial

immunosuppression• Drugs• Radioactive irradiation

PRIMARY IMMUNODEFICIENCIES

• MOST ARE RECESSIVE MUTATION OF SINGLE GENES– Dominant traits have been eliminated from the population– Autosomal genes

• Disease in homozygous children

• Heterozygous children are carriers

– X-linked genes• Single gene defect causes disease in males

• Single gene defect in females renders the affected woman carrier – Mutation in the IFNγ receptor results in binding without

intracellular signaling - dominant

DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium USED FOR VACCINATION

The impact of recessive and dominant mutations in the IFN-γ receptor on monocyte

activation.

Numerous Immunodeficiency loci reside on the X chromosome

CGD: Chronic Granulomatous Disease

WAS: Wiscott-Aldrich Syndrome

SCID: Severe Combined Immunodeficiency

XLA: X-linked Agammaglobulinemia

XLP: X-linked Lymphoproliferative Disease

XLHM: X-linked Hyper-IgM Syndrome

TYPES OF INHERITED IMMUNE DEFICIENCIES

• ANTIBODY DEFICIENCY

• - recurrent sinopulmonary and GI infections beginning after 3-4 mo.

– B cell development• (XLA, IgA deficiency)

– B – T cell collaborations • CD40 ligand, hyper IgM

• T CELL DEFICIENCY

• - SCID, opportunistic infections beginning early in infancy

– T cell development• IL-7/Jak3• RAG-1 RAG-2• Artemis

– Thymus epithelial cells• DiGeorge syndrome

– Purin catabolism– DNS repair enzyme

defect– MHC class II synthesis

blockade

• PHAGOCYTIC SYSTEM– CD18 (CR3, CR4, LFA1)– NADPH oxidase (CGD)– Vesicular fusion

• COMPLEMENT SYSTEM• some infections,

primarily with encapsulated organisms and Neisseriae

– Soluble and membrane factors

– C3– C1 – C4– Complement inhibitors

TYPES OF INHERITED IMMUNE DEFICIENCIES 2.

Immunodeficiencies caused by B-cell defects

Approx. 70% of all IDs

Late Manifestation (7-9 month)

Increased sensitivity to:Encapsulated bacteriaStreptococcus pneumoniaeHaemophylus influenzae

Infection by Enterovirus, parasites

SERUM IG LEVELS AS THE DEVELOPMENT OF THE IMMUNE SYSTEM PROGRESSES

„Who are missing?”

• X-LINKED AGAMMAGLOBULINEMIA XLA(Bruton’s agammaglobulinemia) 1:200,000

Symptoms– First few months of life is relatively normal (maternal Ig)– Tonsils are small, lymph nodes are barely palpable– Recurrent infection of sinuses and of the middle ear.

Pneumonia.– Pyogenic bacteria – permanent tissue demage caused by

enzyme release from bacteria and phagocytes bronchiectasis, chronic lung disease

• Haemophilusinfluenzae, Streptococcus pneumoniae, Staphylococcus aureus,

– Oral polio vaccine disseminate and cause poliomyelitis– T-cell responses to intracellular bacteria is normal

(mycobacteria) – Lack of mature B cells plasma cells in the periphery

ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA

• X-LINKED AGAMMAGLOBULINEMIA XLA(Bruton’s agammaglobulinemia)

Genetic defect– Mutation in the Bruton’s tyrosine kinase, essential for B cell

activation and development– NO B CELLS IN THE PERIPHERY – block at pre-B cell stage – Carrier mother XX HEALTHY non-random inactivation of X in B

cells– Son XY DISEASE Son XY HEALTHY– Increased susceptibility to bacteria and enteroviruses

Treatment– monthly injections of Gamma glob. (IVIG)

ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA

When a T-cell defect results in antibody deficiency

X-LINKED HYPER IgM SYNDROME

• HYPER IgM SYNDROME (XLHIM)

Symptoms– Susceptibility to pyogenic bacteria/opportunistic infection

• Sensitivity to pyogenic bacteria Haemophilusinfluenzae, Streptococcus pneumoniae, Staphylococcus aureus

• opportunistic infections

– No specific antibody response to T-dependent antigens• low IgG, IgA, IgE

– No germinal center formation– No leukocytosis but neutropenia– No macrophage activation by T cells CD40 – CD40L

• opportunistic infections• sores and blisters in the mouth and throat• injection of GM-CSF (GMCSF is produced by macrophages)

DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T CELL HELP

Lack of germinal centers in lymph nodes ofX-linked Hyper-IgM syndrome patients

• HYPER IgM SYNDROME XLHIM

Genetic defect

Defect of the DC40L membrane receptor gene– X-linked, disease in males

Treatment

– antibiotics,

– monthly injections of Gamma glob. (IVIG)

– injection of GM-CSF (neutropenia)

DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T CELL HELP

•HYPER IgM SYNDROME (Autosomal)

-Intrinsic B cell defect, activation induced deaiminase (AID) deficiency. Cytidine uridine conversion. -The enyme is involved in affinity maturation and Ig. class switch - Lack of opportunistic infections

SELECTIVE IgA DEFICIENCY

1/800- Chronic lung disease, - Tendency to develop respiratory and gastrointestinal allergies and autoimmunity- Over 40% of patients have anti-IgA antibodies – blood products containing IgA can cause severe allergic response. -Some are related to MHC class III region

T CELL IMMUNODEFICIENCIES

• Persistent and recurrent infections with a broader range of pathogens than patients with B cell deficiences

• Neither T cell-dependent antibody response nor cellular immunity are functional

• T-, B+ NK- SCID• T- B- NK+

DEFECT IN T CELL FUNCTIONST cells are involved in all aspects of adaptive immunity

SEVERE COMBINED IMMUNODEFICIENCYSCID

• Small body weight, failure to thrive• Persistent and recurrent infections with a broader range of pathogens than patients

with B cell deficiences• Opportunistic infections (Candida albicans, Pneumocystis carnii pneumonia)

X-LINKED SEVERE COMBINED IMMUNODEFICIENCYSCID (Over 50% of cases)

Symptoms

Candida albicans infection in children with SCID

The Hart shadow is clearly visibleIn the absence of the thymus

Normal SCID

• X-SCID – The common γ-chain of interleukin receptors is mutated IL-7 receptor– Part of IL2,4,7,9, 15, 21 Receptor

• Autosomal SCID – mutation of Jak3 kinase IL-7 receptor-mediated signaling • Defect in the catabolism of purin bases – autosomal (T- B- NK+)

– Adenosine deaminase (ADA) mutation – mental retardation – Purin nucleotide phosphorilase (PNP)

• Accumulation of purin metabolites • Highly toxiC for developing lymphocytes,

• Mutation of RAG enzymes – autosomal (Omen syndrome T- B- SCID)– No or little somatic gene rearrangement (RAPIDLY FATAL)– No circulating peripheral lymphocytes or very narrow repertoire

• Mutation of a DNA repair enzyme – autosomal – DNA-dependent protein kinase (DNA-PK) involved in the cleavage of hairpins in

somatic gene rearrangement • Bare lymphocyte syndrome – inhibited MHC synthesis

– No CD4+ T cell response– CIITA co-activátor, RFX promoter binding protein or other transcription factor

mutation• DiGeorge szyndrome

– Development of thymic epithelial cells is inhibited – T cell development is inhibited

SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects

• Defect in the catabolism of purin bases – autosomal (T- B- NK+)– Adenosine deaminase

(ADA) mutation – mental retardation

– Purin nucleotide phosphorilase (PNP)

• Accumulation of purin metabolites

• Highly toxic for developing T lymphocytes, less toxic for developing B lymphocytes

SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects

ADA conc. A tímuszban kb 10-szeres

Treatment:Bone marrow transplantation, preferably from a Bone marrow transplantation, preferably from a histocompatible siblinghistocompatible siblingGene therapyGene therapy

DiGeorge Syndrome

• Hypoparathyroidism• Thymic hypoplasia leading to variable

immunodeficiency Peripheral T cells missing or greatly reduced

• Opprtunistic infections

• Other features:• Characteristic facial expression• Deletion in 22q11 in > 80%• Affected gene(s) is a transcription factor in the T-box

family called Tbx1

Immunodeficiency caused by defects in B and T cell development

• Wiskott-Aldrich syndrome WAS – X-linked A disease of defective reorganization of the actin cytoskeleton

Symptoms– Thrombocytopenia, small platelet size (decreased production of

platelets in B. Marrow, increased destruction in spleen)– Eczema– No antibodies to carbohydrate antigens (role for T cells?)– pyogenic and opportunistic infections

severe infection with varichella (chicken pox) and herpes simplex (impaired CD8+ T-cell response)

– Rearrangement of cytoskeleton upon T cell activation in the polarized contact with B cells, macrophages and target cells

– Low IgM high IgA, IgE serum levels – Pyogenic bacterial, and opportunistic infections– B cell lymphomas

Genetic defect– Mutation in the WAS protein (WASP) expressed in white blood cells

and megakaryocytesTreatmentBone marrow transplantation

• Wiskott-Aldrich syndrome WAS – X-linked

Thrombocytopenia 40000 /μL + smaller thrombocytes

Loss of microvilli on T cells in Wiskott–Aldrich syndrome.

Scanning electron micrographs of normal lymphocytes (panel a) and lymphocytes from a patient with Wiskott–Aldrich syndrome (panel b). Note that the normal lymphocyte surface is covered with abundant microvilli, which are sparse or absent from the patient's lymphocytes. Photographs courtesy of Dianne Kenney.

Wiskott-Aldrich syndrome WASDefective T/B communication

Expressed in white blood cells and megakaryocytes

Capping of TCR is defective in WASP negative T cells

T cells from wt-mice

T cells from WASP-/- mice

resting anti CD3 treated

• DEFICIENCY OF CD18/LEUKOCYTE ADHESION (LAD)– Common β-subunit of CR3, CR4 and LFA-1– Blocked phagocyte migration from blood to infection site– Inhibited uptake and degradation of opsonized bacteria – Persistant infection with extracellular bacteria

• Pyogenic infections• Defect in wound healing, severe inflammation of the gumsLethal within the first decade of life without bone marrow

transplant

DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS

Omphalitis in

LAD I patient

CHRONIC GRANULOMATOUS DISEASE – CGD (1 million in the US)

Mutation of NADPH oxidase – any of the 4 subunits (gp91 X-linked)No superoxid O2- radical antibacterial activity is compromised Chronic intracellularbacterial or fungal infections – granuloma formationAspergilus pneumoniaIFN-gamma improves resistance. Mechanism??Defect of glucose-6-phosphate dehydrogenase and myeloperoxidase less severe phenotype

Diagnosis: NBT + PMA treatment of neutrophils. Lack of blue colour in CGD

DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS

CGD patient with

skin infections

due to Serratia

marcescens

CHRONIC GRANULOMATOUS DISEASE – CGD

NBT staining of neutrophils

Healthy

CGD Carrier

Phox complex

MUTATION OR FUNCTIONAL INACTIVATION OF SOLUBLE COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY

B-factor

D-faktor

Pyogenic infections immune complex disease

Alternative

Properdin

C5

C6

C7

C8

C9

C3I-factorH-faktor

Classical Lectin

Neisseria-infection immune complex disease

C1Inh

HANE*

Neisseria-infection severe pyogenic infections

Pyogenic infections immune complex disease

C1MBL

MASP

C2C4

*HANE - hereditary angioneurotic edema

Stabilizes alternative C3convertase

Intra va sc ula rhem olysis

(c o m p le m e nt re c e p to r 1)C R1SLE* -

a ssoc ia tion

Pyo g enicinfec tio ns

(De c a y Ac c e le ra ting Fa c to r) (Ho m o lo g o us Re stric tio n Fa c to r) (M e m b ra ne inhib ito r o f Re a c tive Lysis)

DAFHRFM IRL

*SLE- syste m ic lup us e rythe m a to sus

(c o m p le m e nt re c e p to r 3,4)LFA

MUTATION OF MEMBRANE BOUND COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY

MIRL = CD59

DAF accelerates the decay of classical and alternative C3 convertase

• DEFICIENCY OF C3 OR ITS ACTIVATION– Susceptibility to pyogenic bacteria – inefficient opsonization

• DEFICIENCY OF C5-C9– Neisseria – NO complement mediated lysis

• DEFICIENCY OF EARLY C1-C4 – No C3b and C4b fragments No CR1-mediated erythrocyte transport of

immune complexes– Accumulation of immune complexes in blood, lymph, extracellular fluid

deposition in tissues tissue demage macrophage activation inflammation

• DEFICIENCY IN COMPLEMENT INHIBITORY FACTORS– I factor – uncontrolled C3 C3b C3 depletion inefficient opsonization– Decay Accelerating Factor DAF or CD59 MAC inhibitor – autoimmune-like

condition lysis of autologous erythrocytes paroxysmal nocturnal hemoglobulinuria

– C1 inhibitor – uncontrolled activation of the classical pathway vasoactive C2 accumulation of fluid in tissues – epiglottal swelling may lead to death by suffocation

DEFECTS IN COMPLEMENT COMPONENTS IMPAIR ANTIBODY RESPONSES

ACCUMULATION OF IMMUNE COMPLEXES