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

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