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David Dockrell University of Sheffield

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1 David Dockrell University of Sheffield
Immunodeficiency David Dockrell University of Sheffield

2 Overview Review the main components of the immune response to infectious diseases Patterns of infection associated with specific kinds of immunodeficiency Causes of congenital and acquired immunodeficiency Considerations with particular patterns of recurrent infection

3 Immune response to infection: patterns and components

4 Elements in host defence
Physical barriers; skin, mucosal surfaces etc. Ciliary function. Humoral factors; Complement, Collectins, b-defensins etc. Phagocytes; Macrophages, Neutrophils, non-professional phagocytic cells. B-cells and antibody production. T-cells and cell mediated immunity

5 Innate and Adaptive immunity
Recognition of limited number of microbial structures. Recognition of huge range of peptides. Immediate Delayed No memory Memory Conserved pathogen motifs, PAMPS Epitopes Limited number of receptors e.g.. TLR Receptor diversity requires somatic mutation Effectors humoral and phagocytes Antibody and T or B-cells

6 Characteristic patterns of infection are associated with immunodeficiency
T-cells (HIV). Required for Cell Mediated Immunity, prime macrophages to kill intracellular pathogens. Viruses; Herpes viruses-CMV, HSV, VZ, HHV-8, Bacteria; Intracellular -Mycobacteria, Salmonella, Opportunistic, Listeria, Nocardia Encapsulated-S. pneumoniae. Fungi -Yeasts Candida spp., Cryptococcus neoformans, Pneumocystis jirovecii (carinii) Parasites; Spore forming cryptosporidia, Toxoplasma gondii, Intracellular-Leishmania spp., Malignancies esp. EBV associated lymphoma, Cervical intraepithelial neoplasia. Autoimmune diseases; rheumatologic, dermatologic (loss of T-regulatory cells)

7 Characteristic patterns of infection are associated with immunodeficiency
B-cells. Required to produce antibody. Encapsulated bacteria. S. pneumoniae., H. influenzae Enteric pathogens; Salmonella spp., Shigella spp., Campylobacter spp. and Rota viruses Parasites; Giardia lamblia Chronic infections enteroviral meningitis, mycoplasma septic arthritis. Autoimmune phenomena; rheumatologic syndromes, gastroenterologic, thyroid, haematologic. Chronic lung disease; bronchiectesasis, sarcoidosis Malignancies Gastric malignancies, lymphomas.

8 Characteristic patterns of infection are associated with immunodeficiency
Phagocytes. Required to kill bacteria and fungi Bacteria; GPC Staphlyococcus aureus GNB Klebsiellla spp. E. coli Opportunistic e.g.. Pseudomonas aeruginosa. Serratia marcescens, Acinetobacter spp. Fungi -Filamentous fungi ; Aspergillus fumigatus, Yeasts Candida spp.

9 Characteristic patterns of infection are associated with immunodeficiency
Complement deficiency. Impaired opsonisation of encapsulated bacteria. Bacteria; N. meningitidis. Terminal complement components critical for membrane attack complex and deficiency results in chronic and atypical Neisserial infections Other bacteria S. pneumoniae, H. influenzae Deficiency of C1, C2 or C4 associated with increased autoimmune disease especially Systemic Lupus Erythematosus Deficiency of the regulatory protein C1 inhibitor is associated with angioedema Deficiency of mannose binding lectin associated with recrurrent angioedema

10 Characteristic patterns of infection are associated with immunodeficiency
Hyposplenism. Decreased reticuloendothelial dysfunction. Bacteria; Encapsulated. S. pneumoniae, H. influenzae, N. meningitidis. Staphylococcus aureus Salmonella enteritidis, Klebsiella pneumoniae Capnocytophagia canimorsus (DF-2) Parasites. Babesia spp., Malaria spp.

11 Primary Immune Deficiency (PID)

12 Clues to primary immunodeficiency (PID)
Tw or more of the following: ≥ 4 new ear infections/yr.. ≥ 2 serious sinus infections/yr.. ≥2 bouts pneumonia/yr. ≥2 mo. on antimicrobials in year Growth retardation in children Recurrent deep skin or organ abscesses Persistent mu oral thrush (candida infection) or fungal infection of skin Need for intravenous antimicrobials to clear infections ≥2 deep-seated infections or septicemia Family history of primary immunodeficiency Usually profound and present in first few years but exceptions e.g. common variable immunodeficiency present later) adapted from Jefferey Modell Foundation (

13 Phagocyte deficiencies of neutrophils
Chronic granulomatous deficiency -recurrent pulmonary infections and abscesses Leukocyte adhesion deficiency -milder high neutrophil numbers, recurrent infections but not abscesses Myeloperoxidase deficiency -mild recurrent infections Chédiak-Higashi -large lysosomes in neutrophils and neurologic problems Job’s syndrome -recurrent infections, severe eczema and high IgE Cyclic neutropenia -drops in neutrophil counts every 3 weeks associated with infection

14 Chronic granulomatous disease.
XL or AR deficiency in components of the NADPH oxidase complex. Components include gp91phox, p22 phox, p47 phox, p65 phox. Individuals are susceptible to catalase positive organisms which detoxify their own reactive oxygen species, generated during metabolism; Recurrent abscess; odontogenic, respiratory, abdominal, musculoskeletal. Obstructive granuloma; GIT, GU Characteristic organisms Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia Aspergillus fumigatus. Diagnosis Nitroblue tetrazolium test , Flow cytometry for ROS, genetic studies. Treatment prompt antimicrobials , IFN-g, prophylactic TMP-SMX, Itraconazole

15 Lekstrom-Himes et al NEJM 2000: 343; 1703

16 CGD Features Lekstrom-Himes et al NEJM 2000: 343; 1703

17 Susceptibility to intracellular pathogens (mycobacteria etc.)
Lekstrom-Himes et al NEJM 2000: 343; 1703

18 Congenital defects of T- and B- cells
Rosenet al NEJM 1995: 333; 431

19 Hypogmmaglobulinemia
Common variable X-linked (Bruton’s) Onset (years) 10-30 1 B-cells Normal but immature Decreased Lymphoid tissue Nodular hyperplasia Atrophic Block Differentiation Most mutations unidentified a few related to ICOS, TACI) Pre-B cell Bruton’s tyrosine kinase (Btk) Associated Pernicious anemia, Malabsorption, Sarcoid Chronic rheumatologic and CNS

20 Hyper IgM syndrome Majority X-linked Lack CD40 ligand
IgM high, IgA, IgG and IgE low B-cell numbers normal Respiratory and intestinal infections Functional T-cell defect in addition also CMV, PCP, Cryptosporidiosis, Cryptococcal infection and Fungi in addition 50% also low neutrophil (PMN) numbers Distinguish from activated PI3 kinase delta syndrome with IgM, IgG2a ±, lymphopenia, T and B-cells but  transitional (CD19+ CD38+ IgM+) B-cells, recurrent sino-pulmonary infection, herpes virus infection and bronchiectasis

21 IgA deficiency Commonest PID in Northern Europeans; 1: 600 IgA
Occasionally IgG but in 30% IgG2 /4 Often incidental but sometimes recurrent respiratory or gastrointestinal infections Autoimmune phenomena Increased allergic phenomena, including rarely to blood products including IVIG

22 Hypogammaglobulinemia
In adults exclude acquired hypogammaglobulinemia secondary to myeloma, chronic lymphocytic leukemia, malnutrition etc.

23 Congenital defects of T- and B- cells
Rosenet al NEJM 1995: 333; 431

24 T-cell deficiency Congenital thymic aplasia (Di George syndrome)
Autosomal dominant (AD), 22q11.2 chromosomal micro-deletion in 90% Developmental failure of third and fourth pharyngeal pouch Thymic aplasia Absent or few mature T-cells B-cells normal but defective responses to T-cell dependent antigens Other congenital defects Absent of parathyroid glands so low calcium Congenital heart disease, oesophageal fistulae, cleft lip and/or palate Distinguish from other T cell defects Bare lymphocyte (lack HLA I/II and deficient in CD8 or CD4 T-cells) Functional T-cell defects (T-cell receptor, Zap70 tyrosine kinase mutations) Chronic mucocutaneous candidiasis -Persistent mucocutaneous candidiasis and nail changes Acquired HIV, Steroids, other immunosuppressants with transplantation or treatment of autoimmune conditions

25 Severe Combined Immunodeficiency (SCID)
Heterogenous defects Die within 2 years unless haematopoetic stem cell transplantations Severe infections; viruses, fungi Graft versus host disease from mothers T-cells X-linked (XL) SCID (45% SCID) Gamma chain of T-cell growth factor (IL-2) receptor T-cells absent, B-cells normal but hypofunctional, NK low (T-, B+, NK-) Autosomal recessive (AR) SCID Adenosine deaminase (ADA) deficiency (15% SCID) Low T- and B-cell and NK numbers (T-, B-,NK-) treatment gene therapy IL-7Ra (11% SCID) Lack T-cells only (T-, B+, NK+) Janus kinase (JAK) 3 deficiency ((<10% SCID) Like XL SCID T-, B+, NK- Recombinase activating genes T-, B-, NK+ various rare other mutations

26 Other combined immunodeficiency syndromes
Wiskott-Aldrich Syndrome (WAS) XL Lack WS protein, regualtes actin cytoskeleton through binding to Arp2/3 complex Normal T- and B-cell numbers but functional defects with infection or vaccination High IgE (low IgM, IgG vary and high IgA) Clinical features: infections including S. aureus, PCP and Molluscum contagiosum (pox virus) of skin Thrombocytopenia and bleeding Allergic manifestations especially eczema Autoimmune features Malignancy especially of B-cells Ataxia telangiectasia AR defect in ATM gene, encodes a serine/threonine kinase needed for DNA repair following DNA double strand breaks. Acivates DNA damage checkpoint (DNA repair, apoptosis, cell cycle arrest) and many of targets tumor suppressors e.g. p53 Lymphopenia , IgA/IgE±IgG, sinopulmonary infections predominate Neurologic defects ataxia and ocular defects (cerebellar and motor) Telangiectasias; skin and eye Malignancies (hematological) Progeric effects premature aging Bare lymphocyte syndrome Can have B- as well as T-cell defects

27 Defects in innate immunity
NK cells CD16 (CD16+ NK cell reduced) or GATA2 (AD with low NK cells) deficiency Recurrent and severe herpes virus infections; HSV, VZV, EBV Innate signaling defects with normal lymphocyte and phagocyte numbers Pattern recognition receptor (e.g. Toll-like receptor signalling) Deficiency of MyD88, an adaptor protein or IRAK-4 a signalling kinase associated with S. aureus and S. pneumoniae infections in particular NEMO (NF kappa B essential modulator), partial deficiency of inhibitor of kappa B kinase gamma required to activate the transcription factor NFkappaB and allow immune responses Pyogenic infections with S. aureus and S. pneumoniae but also mycobacterial disease Ectodermal dysplasias with skin thickening and conical teeth

28 Useful website for PID

29 Approach to the patient with recurrent infections

30 Tests to assess immune function
Neutrophils(PMN): PMN numbers, morphology (large lysosomes, nuclear morphology), flow cytometry (generation of reactive oxygen species, surface expression of integrins) B-cells: immunoglobulin subsets, B-cell numbers and markers, response to vaccines T-cells: T-cell subsets on lymphocyte cytoflow using surface markers, response to T-cell dependent vaccines Genetic studies or detection of particular proteins by specialised centres to ascertain cause of certain syndromes

31 Recurrent respiratory infections
Smoking Chronic lung disease; COPD, Asthma Bronchiectasis Cystic fibrosis Foreign body (unifocal) Ciliary dysfunction HIV Hypogammaglobulinemia, T-cell dysfunction, Neutropenia or neutrophil dysfunction.

32 Unusual forms of mycobacterial disease
Absence of granulomata. Heavy mycobacterial burden in macrophages. Frequent atypical mycobacterial pathogens isolated. Often extrapulmonary and/or multi site disease. Family history or history anti-TNF therapy. Occasionally invasive salmonella or other intracellular pathogens.

33 Anti-TNF treatment and TB
Appearances on H+E and TUNEL staining with or without Infliximab treatment. NB absent granulomata and reduced macrophage apoptosis Keane et al. NEJM 2001:345; 1703

34 Recurrent meningitis Terminal complement deficiency (C5-8), Properidin. Recurrent Neisserial infections. Frequent, mild, older age, unusual serotypes. CSF leaks. Respiratory pathogens. History trauma, surgery chronic ear or sinus disease. Mollaret’s meningitis. Behcets. Lupus Drugs (NSAIDS, Antibiotics, OKT3)

35 Recurrent skin abscesses
Mostly not associated with immunodeficiency but with recurrent colonization. Rarely associated with immunodeficiency: CGD, MPO deficiency, Neutrophil G6PDH deficiency, Hyper IgE syndrome (Job’s), Wiskott Aldrich, T-cell or B-cell defects. Clues to immunodeficiency severity (size, failure to settle with antibiotics, frequency), onset in infancy, family history, associated infections, unusual organisms, other features of immunodeficiency, oral signs, history of problems with BCG. Recurrent cellulitis; rarely immunodeficiency, chronic eczema, diabetes, tinea pedis, lymphoedema, foreign body, osteomyelitis.

36 Recurrent facial swelling
C1 inhibitor deficiency causes angio-oedema which may be associated with a recurrent abdominal pain but not urticaria, wheezing or hypotension. Precipitants; minor trauma, stress, infections, oestrogens, ACE inhibitors. Congenital (AD) onset in adolescence or acquired (SLE, lymphoreticular malignancy). Screen C4 if low assay C1 inh level and function.

37 Post transplantation infections
Immunodeficency posttransplantation is largely due to T-cell dysfunction. Other problems are related to the premorbid condition, anatomical considerations related to the surgery and impairment of physical barriers. Infection risk varies with time posttransplant. 0-1 months local post-surgical problems; wound site infections, abscesses etc. 1-6 months classic T-cell immunodeficiency infections especially CMV. Defined risk factors. >6 months late infections VZ, CMV bacterial infections

38

39 Immunodeficiency in cancer patients
Usually multifactorial. Major factor is a defect in neutrophil numbers in association with chemotherapy or sometimes malignancy itself. Duration of neutropenia is major factor influencing risk of fungal infection. Longer with AML (acute myeloid leukaemia), Haematopoeitic stem cell transplant (HSCT) etc. Mucosal defences are impaired by mucositis while CVC penetrates cutaneous barriers. Malignancy or therapy may add additional defects e.g.. Impairment of cell mediated immunity with Hodgkin's lymphoma, specific cytotoxics or HSCT.

40 Invasive pulmonary aspergillosis

41 Invasive pulmonary aspergillosis

42 HIV Acquired CD4 T-cell deficiency plus other immune defects of B-cells, CD8 T-cells, macrophages etc.) Remember to test any patient with recurrent infections or symptoms compatible with HIV infection Presents with fever, weight loss , recurrent infections At higher CD4 T-cell counts recurrent respiratory tract infection, TB, recurrent shingles (herpes zoster). As CD4 count drops < 350 cells/ml recurrent mucocutaneous candidiasis When CD4 count < 200 cells/ml develop acquired immunodeficiency syndrome (AIDS) opportunistic infections: PCP, CMV, oesophageal candidiasis, cryptococcosis, toxoplasma encephalitis malignancies such as Kaposi's sarcoma (human herpesvirus 8 ) and lymphoma

43 Periodic fever syndromes
Recurrent fever, systemic inflammation and elevated acute phase response (e.g. C-reactive protein) Occasionally not due to infections but an auto-inflammatory syndrome Familial Mediterranean fever (AR) MEFV gene mutations. MEFV encodes pyrin, asuppressor of caspase 1 and so IL-1 production Fever, arthritis, pleuritis, peritonitis, attacks last a few days Complicated by AA amyloidosis Treatment colchicine or anikinra (IL-1 antagonist) Mevalonate kinase /hyper IgD syndrome (AR) Fever, serositis, lymphadenopathy, diarrhoea and skin rashes Elevated IgA and IgD and CRP Treatment with anakinra but resistant to steroids and colchicine TNF receptor associated periodic syndrome (TRAPS)/Hibernean fever (AD) Low levels soluble TNF receptor Fever, serositis, arthritis, rashes, more prolonged attacks > 1 week Elevated IgA, CRP Complicated by amyloidosis Treated with anti-TNF or anti-IL-1 (ankinra ) therapy)

44 Conclusions The pattern of infections can give clues to the part of the immune response that is dysfunctional in patients with recurring infection Specific patterns for patients with T-cell, B-cell, neutrophil , macrophage or complement defects Primary immune deficiencies (PID) are rare, most present in infancy and require specialised centres to help make the correct diagnosis Acquired immune deficiency results from cancer, chemotherapy, immunosuppressants or HIV. Always exclude HIV as a cause of immune deficiency


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