Immunology and Immunodeficiency for the Hematologist-Oncologist

Immunology and Immunodeficiency for the Hematologist-Oncologist
Header Immunology and Immunodeficiency for the Hematologist-Oncologist Subhead Sung-Yun Pai MD

Some points Having taken the course myself for board recertification, I can personally state the course prepares you well A bunch of this stuff you already know and the stuff you probably don’t (i.e. lymphocyte biology) only makes up ~5% of the questions maximum * in the corner means there are some content specs on that slide I tinker with this lecture every time in response to previous years’ feedback

Objectives Identify the cellular basis of immune compromise in patients undergoing chemotherapy or HSCT, the classes of infections associated with various cellular deficiencies, and general principles of management of infections in immunocompromised hosts Identify the normal pattern of development of the adaptive immune system in children and the presentation and diagnostic features of specific congenital deficiencies of adaptive immunity

Content to be reviewed Infections in the immunocompromised host
2 Content to be reviewed Infections in the immunocompromised host Normal T and B cell development and function and evaluation of recurrent infection Congenital immunodeficiency states made easy (2 slides on AIDS)

natural killer (NK) cells
3 Phagocytosis Produce bactericidal reactive oxygen species neutrophils INNATE Phagocytosis Antigen presentation Clearance of debris macrophages dendritic cells Antigen presentation Phagocytosis natural killer (NK) cells Kill virally infected cells Kill tumor or foreign cells CD16/ 56 ADAPT IVE CD4 Cellular immunity Help B cells class switch Help CD8 T cells kill CD3/CD4 T cell thymus CD8 CD3/CD8 T cell Cellular immunity Cytolytic activity Make antibody Antibodies opsonize bacteria Antigen presentation CD19 B cells

4 INNATE ADAPT IVE BACTERIA neutrophils FUNGI macrophages
contribute to all dendritic cells natural killer (NK) cells VIRUSES (esp DNA viruses) CD16/ 56 ADAPT IVE CD4 CD3/CD4 T cell thymus VIRUSES PNEUMOCYSTIS FUNGI CD8 CD3/CD8 T cell BACTERIA (esp encapsulated) CD19 B cells

What host factors cause immunocompromise?
5 What host factors cause immunocompromise? Loss of physical barriers Medication Acquired or congenital defects in cell number Acquired or congenital defects in cell function

Chemotherapy and HSCT cause multiple hits to the immune system
6 Chemotherapy and HSCT cause multiple hits to the immune system Loss of physical barriers mucosal impairment central venous catheters etc. Medication corticosteroids (ALL, GVHD) specific immunosuppressants (CsA, others) antibody therapy (ATG, rituximab, alemtuzumab) Acquired or congenital defects in cell number neutropenia, CD4 lymphopenia Acquired or congenital defects in cell function

Timing of infections post-allogeneic HSCT
* 7 Timing of infections post-allogeneic HSCT Pre-engraftment (day 0-30) Post-engraftment (early day ) Post-engraftment (late day >100) BACTERIA Gram + Gram - Anaerobes Same Esp catheter associated Encapsulated organisms* FUNGI Candida Aspergillus Aspergillus* Aspergillus* VIRUSES HSV Respiratory CMV* Respiratory EBV-LPD VZV CMV* Respiratory EBV-LPD OTHER Pneumocystis Toxoplasma Pneumocystis Toxoplasma DEFECT profound neutropenia catheter lymphopenia esp CD4 T cell suppressive meds aGVHD catheter lymphopenia esp CD4 T cell suppressive meds cGVHD Poor Ig production * risk enhanced or associated with GVHD acute or chronic and its treatment

Management of infection in immunocompromised hosts
8 Management of infection in immunocompromised hosts Bacterial infection Fungal infection Pneumocystis Viral infection (especially DNA viruses) Note: these are not meant to be the absolute most up to date recommendations and are geared towards what I think are testable principles supported by evidence

* 9 Bacterial infection In chemo/HSCT patients bacteria are derived from endogenous flora, in context of mucosal and skin barrier disruption Epidemiology has shifted from GNR to GPC GNR: E. coli, Pseudomonas, Enterobacter, Klebsiella, Serratia, other GPC: Staph aureus, coagulase negative Staph, alpha-hemolytic strep (S. mitis, S. sanguis), Enterococcus anaerobes: Bacteroides, Clostridium Association of Ara-C and alpha-hemolytic strep with ARDS and rapidly evolving sepsis syndrome Keep in mind resistant organisms and local pattern methicillin-resistant S. aureus, vancomycin-resistant enterococcus inducible plasmids encoding extended spectrum beta lactamases causing resistance after exposure to cephalosporins in Enterobacter and other GNR

* Bacterial infection 10 Prophylaxis: Principles of empiric therapy:
Randomized controlled trials and meta-analyses demonstrate decrease in infection and possibly improved survival with prophylactic antibiotics in neutropenic cancer patients Evidence for improvement in mortality is less clear in HSCT patients Benefits of use must be weighed against risk of developing resistance Principles of empiric therapy: Fever and neutropenia in setting of chemotherapy is an emergency Instituting immediate therapy without awaiting culture results is standard Physical examination to identify localizing source must be performed but rarely identifies cause Regimen should cover enteric GNR, S. aureus, other gram positives monotherapy is the standard recommendation (3rd gen cephalosporin, carbapenem, piperacillin/tazobactam) Additional agents (aminoglycoside, quinolone, more GPC coverage) upfront or delayed depending on clinical circumstances Stopping antibiotics after 7 days in persistently neutropenic patients leads to about 40% of patients developing fever or hypotension

Random interlude about the spleen
* 11 Random interlude about the spleen Several immunological functions of the spleen Site of filtration and innate immunity Opsonization of encapsulated organisms Consumption by macrophages Site of primary and secondary adaptive immune responses T cells get primed by APC T cells interact with B cells, which make specific IgM Activated follicular B cells mature, class switch, undergo affinity maturation Site of specialized B cell population Marginal zone B cells that respond to polysaccharide antigens and are generated by 2 years of age

Anatomic/functional asplenia
* 12 Anatomic/functional asplenia Prophylaxis: oral penicillin twice a day for <5 years old Lifelong for anyone who has had post-splenectomy sepsis Consider for >5 years old for first 1-2 years after splenectomy Principles of empiric therapy: Give antibiotics within 2 hours, at home if >2h from hospital For hospital: parenteral 3rd or greater generation cephalosporin For home: amoxicillin 45 mg/kg (max 2g) or levofloxacin 10 mg/kg (max 750 mg) Principles of vaccination: Special schedules for pneumococcus, HiB, meningococcus ACIP recommendations for immunocompromised (functional or anatomic asplenia, including sickle cell disease, HIV+, CSF leak, cochlear implant) 2012 Catch up everyone with PCV13 if PCV13 naïve Catch up everyone with PPSV23 if PPSV23 naïve If naïve to both, give PCV13 then 8 weeks later PPSV23 2nd dose of PPSV23 after 5 years If PPSV23 in past, but naïve to PCV13, give PCV13 >8 weeks from last PPSV23

* 13 Fungal infection Two major populations at risk, with propensity for different fungi profound and long neutropenia (Candida, Aspergillus, others) defective cellular immunity (Cryptococcus, Histoplasma, Coccidiodes) Other rarer fungi include: Fusarium, Mucor, Trichosporon, dematiaceous molds Unlike bacterial infection, these are not endogenous but patients become colonized due to exposure and modulation of normal flora

* Fungal infection 14 Prophylaxis: Principles of empiric therapy:
Large trials have shown decrease in fungal infections in adults during leukemia induction or undergoing HSCT Current IDSA recommendations are to use an azole (fluconazole, itraconazole, voriconazole, posaconazole) or echinocandin (micafungin, caspofungin) for prevention of Candidiasis during induction or HSCT (neutropenia >7 days) Patients with CGD benefit from prophylactic treatment Principles of empiric therapy: Empiric anti-fungal therapy is standard for persistent fever and neutropenia (4 to 7 days) Other possible signs of fungal disease include: nasal or sinus tenderness, painful swallowing, pulmonary infiltrates Therapy should be directed against Candida and Aspergillus, and no one agent is specifically recommended. Choice of empiric agent should take into account prophylactic regimen, known colonization, individual patient profile and local epidemiology

Pneumocystis jirovecii
* 15 Pneumocystis jirovecii (formerly called Pneumocystis carinii) risk factors for Pneumocystis pneumonia include: HIV infection with CD4 count <200 HSCT recipients cancer especially leukemia solid organ transplant recipients glucocorticoids, chemo or other immunosuppressants primary immunodeficiency especially SCID (renamed because P. jirovecii infects humans while P. carinii infects other mammals, like rodents)

Pneumocystis jirovecii
* 16 Pneumocystis jirovecii Prophylaxis: Trimethoprim-sulfamethoxazole 150 mg TMP/m2/day (5 mg/kg/day) divided BID TIW consecutive days most tested Alternatives to TMP/SMX: atovaquone, dapsone, aerosolized pentamidine, intravenous pentamidine, clindamycin plus primaquine, sulfadoxine plus pyrimethamine few if any studies in non-HIV patients comparing efficacy Treatment: Trimethoprim-sulfamethoxazole 15-20 mg/kg/day divided TID-QID, PO or IV for days adjunctive corticosteroids shown to be effective in HIV, less certain in non-HIV mild disease: atovaquone, severe disease: pentamidine IV, clindamycin plus primaquine

* 17 Viral infection Patients with poor cell mediated immunity are at high risk for infection due to DNA viruses post-BMT solid organ transplant HIV primary immunodeficiency CMV, HSV, VZV, EBV can all cause disease from primary exposure, or from reactivation of latent infection

* Viral infection 18 Cytomegalovirus Prophylaxis Treatment
Herpes family DNA virus that causes asymptomatic or self-limited flu/mononucleosis illness in competent host Can be passed through organs, blood, breastmilk, saliva, urine Disease manifests as viremia, interstitial pneumonitis, colitis, retinitis, hepatitis, esophagitis/gastritis Asymptomatic shedding in urine and saliva can occur Organ disease and viremia/blood antigenemia are not always correlated Prophylaxis using only blood products from CMV negative donors OR leukofiltration in BMT setting, treatment with ganciclovir prevents interstitial pneumonia Treatment ganciclovir 5 mg/kg/dose IV twice a day for 2 weeks valganciclovir orally, dosing is not well established in children foscarnet 180 mg/kg/day divided twice or three times a day for 2 weeks cidofovir does have activity against CMV

* Viral infection 19 Herpes simplex virus Prophylaxis Treatment
Herpes family DNA virus HSV-1 and HSV-2 that establishes latency High prevalence of seropositivity in adults, less so in children Before routine prophylaxis as many as 70-80% of patients reactivated during HSCT Can present as worsening or persistent mucositis, fever Prophylaxis Acyclovir during HSCT pancytopenic period, may extend in particular cases Ganciclovir also has activity, if patient is on ganciclovir for CMV Treatment Acyclovir 10 mg/kg IV every 8 hours, in >12y or adult 5 mg/kg IV every 8 hours Foscarnet if resistant recommendation for adults 40 mg/kg IV every 8 hours

* Viral infection 20 Varicella zoster (Herpes zoster) Prophylaxis
Herpes family DNA virus that causes primary varicella and shingles Primary or reactivation disease can be severe in immunocompromised patients, causing hepatitis, pneumonitis, encephalitis Prophylaxis universal vaccination began in US in 1995 acyclovir, valacyclovir, famciclovir can all be used to prevent VZV reactivation in the absence of Varicella specific Ig (VZIG), pooled IVIg can be used to prevent disease after exposure in non-immune children up to 96h post Treatment high dose acyclovir, 1500 mg/m2/day IV divided every 8 hours, adjust for renal insufficiency and hydrate oral acyclovir or other anti-virals

Lymphocytes contribute to both innate and adaptive immune systems
* 22 Lymphocytes contribute to both innate and adaptive immune systems CD16/56 NK cell INNATE CD4 helper T cell thymus CD8 cytolytic (killer) T cell ADAPTIVE CD19 B cell

Major arms of the adaptive immune system
* 23 Major arms of the adaptive immune system Cellular immunity T cells (most are a/b T cells) Express TCR with CD3 complex (TCRa, TCRb, CD3zz, CD3ed, CD3eg) -CD4 T cells see antigens complexed to MHC class II on APC helper function cooperate with B cells to induce class switching control opportunistic infection cancer surveillance regulatory functions -CD8 T cells see antigen complexed to MHC class I on APC cytolytic function kill virally infected cells Humoral immunity B cells Produce antibody IgM and IgD first IgG, IgA, IgE only after class switching additional mutations in Ig locus occur—B cells carrying receptors with higher affinity are selected (affinity maturation) Antibodies opsonize bacteria particularly important for respiratory pathogens skin flora encapsulated organisms

* 24 What holes are generated in the immune system when lymphocytes are absent or do not function? Cellular immunity T cells -CD4 T cells loss of Ig production opportunistic infections fungal infections viral infections -CD8 T cells lack of killer function viral infection especially DNA viruses cancer surveillance Humoral immunity B cells Produce antibody Antibodies opsonize bacteria inability to opsonize bacteria especially respiratory, skin, encapsulated organisms

How does the adaptive immune system develop?
* 25 Bone marrow Thymus Blood preBCR PreT T TCR rearrangement proliferation DP TCRab TCRb CD4- CD8- CD4+ CD8+ OR T TCR CD4 CD8 CD3 HSC HSC BCR heavy chain (IgH) rearrangement BCR light chain (IgL, IgK) rearrangement ProB PreB immB IgM CD34+ CD19+ CD10+ CD34- CD20+ IgM B CD19+ IgD Spleen

How does the adaptive immune system adapt?
* 26 Antigen Effector fxn Most die Mem TCR CD4 BETTER FASTER STRONGER Memory response T TCR T CD8 Mem Ig class switch Affinity maturation Spleen & Lymph node Antigen IgM CD19 IgG IgA IgM B IgD

How to measure immunologic function?
* 27 How to measure immunologic function? Enumeration total lymphocytes, subsets absolute lymphocyte count CD3 = T cells CD4 = helper T cells CD8 = cytolytic T cells CD19 = B cells CD16 or CD56 = natural killer (NK) cells

Normal values for lymphocyte subsets in children and adults
* 28 Normal values for lymphocyte subsets in children and adults ALC, CD3 and CD4 counts are higher in young children B cell numbers are maximal 2 months to 2 years then contract NK cell numbers are pretty stable Reprinted from Journal of Pediatrics, 130/3, Comans-Bitter, et, Immunopheotyping of blood lymphocytes in childhood reference values for lymphocytes subpopulations, , 1997, with permission from Elsevier

Infant versus adult lymphocyte subsets
* 29 Infant versus adult lymphocyte subsets Adult ALC ( ) CD ( ) CD ( ) CD8 400 ( ) CD ( ) CD (90-600) Infant (1 wk to 2 mo) ALC ( ) CD ( ) CD ( ) CD ( ) CD ( ) CD ( ) ALC of less than in an infant is highly abnormal. Reprinted from Journal of Pediatrics, 130/3, Comans-Bitter, et, Immunopheotyping of blood lymphocytes in childhood reference values for lymphocytes subpopulations, , 1997, with permission from Elsevier

* 30 How to measure immunologic function? Non-specific function T cells Proliferation to mitogens phytohemagglutinin (PHA) pokeweed mitogen (PWM) concanavalin A (ConA) B cells Total IgG, IgA, IgM IgG subclasses IgG1, IgG2, IgG3, IgG4 Remember that antibody production also requires intact T cell function

* 31 How to measure immunologic function? Specific function T cells Proliferation to antigen tetanus, Candida Skin testing Candida control B cells Antigen-specific antibody protein Ag (tetanus, hepBsAg) carbohydrate antigen (blood group, pneumovax) Remember that antibody production also requires intact T cell function

Immunoglobulins for dummies
* 32 Immunoglobulins for dummies Class Structure Affinity Placental transfer? % IgM Pentameric Low affinity No 5-10% IgG Monomeric High affinity Yes 75-85% IgA Mono-, dimeric Low affinity No 5-15% * IgD does not require class switching, no clear function * Levels of IgE not necessarily part of an immunodeficiency work-up

Normal immunoglobulin for age (IgG)
* 33 Normal immunoglobulin for age (IgG) physiologic nadir 2-6 months values from Jolliff Clin Chem 1982

Normal immunoglobulin for age (IgA)
* 34 Normal immunoglobulin for age (IgA) values from Jolliff Clin Chem 1982

Normal immunoglobulin for age (IgM)
* 35 Normal immunoglobulin for age (IgM) values from Jolliff Clin Chem 1982

Take home points about normal lymphoid development
* 36 Take home points about normal lymphoid development infants and children have higher ALC and T cell numbers than adults IgG crosses the placenta physiologic nadir of IgG occurs around 2-6 months

Congenital Immunodeficiency in one slide
* 38 Congenital Immunodeficiency in one slide Absent Present/Broken T cells B cells Neutrophils SCID Ex: WAS XLA Ex: CVID SCN Ex: CGD Note: patients lacking NK cells have been described but are very rare

Congenital Immunodeficiency
* 39 Congenital Immunodeficiency Failure of T cell development SCID (severe combined immunodeficiency) Failure of B cell development XLA (X-linked agammaglobulinemia) Functional T, B, or combined defects T and B cells present but not fully functional Wiskott-Aldrich syndrome (WAS) X-linked Hyper-IgM syndrome (CD40LG) X-linked lymphoproliferative disease (XLP) Common variable immunodeficiency (CVID) Autoimmune lymphoproliferative syndrome (ALPS)

* 41 Definition of SCID Severe combined immunodeficiency is “combined” because if you lack T cells, you automatically lack B cell function Absence of functional autologous T cells is uniform B cells can be present or absent B cells even if present usually don’t function, i.e. no specific antibody production generally fatal before age 2 due to overwhelming infection

* When to suspect SCID 42 Symptoms Signs/Lab findings
Failure to thrive Chronic diarrhea Recurrent infections Signs/Lab findings thrush absence of lymphoid tissue opportunistic infection ex: PCP low or absent T cells lack of immunoglobulins lack of thymic shadow Associated findings FH ex: X-linked neurologic (ADA) cardiac (DiGeorge)

* How to diagnose SCID 43 Check ALC, send lymphocyte subsets
T cells very low or absent Send lymphocyte proliferation studies Absent or very low proliferation of T cells to mitogens Total IgG, IgA, IgM and specific Ab if vaccinated

SCID with normal ALC? SCID with T cells present?
* 44 SCID with normal ALC? SCID with T cells present? 4 month old boy with chronic cough and FTT. Diagnosed with PCP. CBC: WBC 12 60% polys 35% lymphs ANC = 7200 ALC = 4200 ( ) CD3 = ( ) CD4 = 8 ( ) CD8 = ( ) CD19 = ( ) CD56= 15 ( ) FISH XX/XY = 2% XX proliferation to mitogens: flat IgG 87 ( )

* How to diagnose SCID 45 Check ALC, send lymphocyte subsets
Because B cells can be present, normal ALC does not rule out SCID Because maternal engraftment can occur, presence of T cells does not rule out SCID Send lymphocyte proliferation studies Maternal T cells do not proliferate. Normal proliferation rules out classic SCID. Total IgG, IgA, IgM and specific Ab if vaccinated Molecular defect can be narrowed down based on lymphocyte phenotype: T-B+ (can be NK - or +) T-B- (can be NK - or +)

* T- B+ SCID 46 Molecular defects:
cytokine common gamma chain (IL2RG, c, CD132) JAK3 (JAK3, Janus kinase 3) IL-7 receptor alpha chain (IL7R, IL-7R, CD127) B cells are present but receive no help, generally do not produce antibody c has X-linked inheritance, accounts for about 1/3 of all SCID JAK3 and IL-7R are autosomal recessive

Lack of growth factor signaling leads to absence of T cells
* 47 Lack of growth factor signaling leads to absence of T cells c IL-7R IL-2 IL-7 Jak3 c IL-4 c Jak3 Jak3 c Jak3 IL-15 Jak3 c IL-21 Jak3 c IL-9

Normal adaptive immune system development
48 Normal adaptive immune system development Blood Bone marrow Thymus T TCR CD4 CD8 CD3 HSC HSC proliferation ProB TCR rearrangement BCR (Ig) rearrangement CD3 PreB preBCR BCR signaling IgM Spleen CD19 IgM immB B IgD

Lack of cytokine signaling causes loss of T cells
49 Lack of cytokine signaling causes loss of T cells Blood Bone marrow Thymus X HSC HSC proliferation ProB TCR rearrangement BCR (Ig) rearrangement PreB preBCR BCR signaling IgM Spleen CD19 IgM immB B IgD

* T- B- SCID 50 Molecular defects: Adenosine deaminase (ADA)
Recombinase activating gene 1, gene 2 (RAG1, RAG2) Artemis (DCLRE1C, DNA crosslink repair 1C), other DNA repair enzymes All autosomal recessive inheritance RAG1/2, Artemis have NK+ phenotype ADA deficiency generally causes NK- phenotype

Lack of rearrangement machinery leads to absence of both T and B cells
* 51 RAG Artemis TCR/BCR Lack of rearrangement machinery leads to absence of both T and B cells

Lack of rearrangement machinery leads to absence of both T and B cells
52 Lack of rearrangement machinery leads to absence of both T and B cells Blood Bone marrow Thymus X TCR rearrangement HSC HSC ProB X BCR (Ig) rearrangement proliferation Spleen

* 53 dATP dAdenosine dInosine Hypoxanthine Xanthine Uric acid ADA PNP Accumulation of toxic metabolites leads to absence of all lymphocytes, T, B, NK

54 TCR/BCR c dATP ADA PNP dAdenosine dInosine IL-21 Hypoxanthine
RAG Artemis TCR/BCR Jak3 IL-7 c dATP dAdenosine dInosine Hypoxanthine Xanthine Uric acid ADA PNP IL-2 IL-4 IL-15 IL-21 IL-9

Diagnosis and management of SCID
* 55 Diagnosis and management of SCID supportive management protection from infection IgG replacement aggressive diagnosis and prompt treatment of infection prophylaxis against Pneumocystis ALL BLOOD PRODUCTS MUST BE IRRADIATED to avoid fatal transfusion-associated GVHD Consider enzyme replacement with PEG-ADA for ADA deficient patients Immediate referral for curative treatment i.e. HSCT* * except complete DiGeorge, which is often treated with thymic transplant

SCID and HSCT for boards purposes
* 56 SCID and HSCT for boards purposes a variety of donors and conditioning approaches can be used to cure SCID with HSCT donor conditioning? T cell depletion? *matched sibling no no haploidentical no YES parent to prevent lethal GVHD unrelated YES either

Take home points about SCID
* 57 Take home points about SCID definition of SCID is lack of FUNCTIONAL AUTOLOGOUS T cells an ALC of <2000 in an infant is very abnormal maternal engraftment is common i.e. presence of T cells does NOT rule out SCID maternal T cells will not proliferate B cells even if present do not function i.e. SCID is in differential of very low IgG inheritance may be X-linked or AR lack of all lymphocytes (T, B, NK) should make you think of ADA

58 * Congenital Immunodeficiency Failure of T cell development SCID (severe combined immunodeficiency) Failure of B cell development XLA (X-linked agammaglobulinemia) Functional T, B, or combined defects T and B cells present but not fully functional Wiskott-Aldrich syndrome (WAS) X-linked Hyper-IgM syndrome (CD40LG) X-linked lymphoproliferative disease (XLP) Common variable immunodeficiency (CVID) Autoimmune lymphoproliferative syndrome (ALPS)

X-linked agammaglobulinemia (XLA)
59 * X-linked agammaglobulinemia (XLA) X-linked disorder of B cell development due to mutation of the BTK (Bruton’s tyrosine kinase) gene which signals downstream of the pre-B cell receptor B cell development is arrested in the bone marrow at the pre-B cell stage resulting in complete absence of peripheral B cells IgG levels fall after maternal IgG naturally declines, pyogenic infections with bacteria occur starting 6-9 months prone to chronic enteroviral meningoencephalitis avoid live virus vaccines

Normal adaptive immune system development
60 Normal adaptive immune system development Blood Bone marrow Thymus T TCR CD4 CD8 CD3 HSC HSC proliferation ProB TCR rearrangement BCR (Ig) rearrangement CD3 PreB preBCR BCR signaling IgM Spleen CD19 IgM immB B IgD

Loss of BCR signaling abolishes B cell development
61 Loss of BCR signaling abolishes B cell development Blood Bone marrow Thymus T TCR CD4 CD8 CD3 proliferation HSC HSC ProB TCR rearrangement BCR (Ig) rearrangement CD3 PreB preBCR X BCR signaling IgM Spleen

X-linked agammaglobulinemia (XLA)
* 62 X-linked agammaglobulinemia (XLA) laboratory shows absence of CD19 cells on lymphocyte subsets, low to absent IgA, low to absent IgM, low to absent IgG depending on age (placental transfer) T cell immunity (T cell numbers, skin reaction, proliferation to mitogens, control of opportunistic infections) is intact mainstay of treatment is IgG replacement with dramatic decrease in incidence of infections

Wiskott-Aldrich syndrome (WAS)
* 64 Wiskott-Aldrich syndrome (WAS) X-linked disorder due to mutation of the WAS protein (WAS, WASP) gene classic triad of immunodeficiency, eczema and thrombocytopenia with small platelets (ex: MPV 4-5 compared to normal about 7-8 fl) not all patients especially when young manifest all parts of the triad, in particular, immune defect tends to worsen with time most boys die by young adulthood from bleeding, infection, autoimmunity or lymphoma

* 65 Wiskott-Aldrich syndrome (WAS) immune defect is combined T and B typically normal to low T and normal B cell numbers T cells can be functionally abnormal abnormal proliferation to mitogen abnormal proliferation to antigen B cell function more often abnormal than T poor specific antibody production classically lacks carbohydrate responses i.e. isohemagglutinins, pneumovax Total IgG declines over time Allergic manifestations including high IgE also seen

* 66 Wiskott-Aldrich syndrome (WAS) not all WASP mutations lead to WAS complete lack of WAS protein usually leads to WAS missense mutations with detectable protein may lead to X-linked thrombocytopenia (XLT) small low platelets no or mild eczema normal immune function some patients may develop autoimmunity missense activating mutations in GTPase binding domain X-linked neutropenia (XLN) normal platelets, lymphocytes, no eczema severe neutropenia, with variable other findings (myelodysplasia, large platelets, reversal of CD4/CD8 ratio)

* 67 Wiskott-Aldrich syndrome (WAS) diagnosis in the old days made by non-random X-linked inactivation in appropriate clinical setting, now WAS protein levels and gene sequencing splenectomy can correct thrombocytopenia for years late manifestations include immune thrombocytopenia (may occur even after splenectomy), autoimmune arthritis, vasculitis, lymphoma supportive therapy includes Ig replacement, platelet transfusion, management of immune complications, treatment of infections curable by early well-matched HSCT

Somatic hypermutation
* 68 Activated CD4+ T cell Hyper-IgM syndromes Proliferation Cytokines Activation of DC share in common defects in switching from IgM to other isotypes process is dependent on CD40L on T cells (expressed on activated CD4+ T cells) interacting with CD40 on B cells (leads to class switching) most common form is an X-linked disorder due to defect in CD40 ligand (CD40LG, CD40L, CD154) gene hence boys have combined B and T cell defect with primary manifestation of hypogammaglobulinemia, low IgG, low IgA and normal or high IgM CD40L CD40 Maturation Class switching Somatic hypermutation Naïve IgM+ B cell

(X-linked, CD40LG deficiency)
* 69 Hyper-IgM syndromes (X-linked, CD40LG deficiency) infectious profile of recurrent bacterial infections (low IgG), opportunistic infections such as PCP, cryptosporidium, histoplasma (poor CD4 cell function) lab tests show normal T and B cell numbers, low IgG, low IgA, normal to high IgM, low CD40L expression after stimulation of T cells in vitro, no production of specific IgG after vaccination curable by HSCT

X-linked lymphoproliferative disease (XLP)
* 70 X-linked lymphoproliferative disease (XLP) X-linked disorder due to mutations in the SAP gene (SLAM associated protein, SH2D1A), an adaptor protein that associates with the SLAM family of receptors on T, B, NK and other cells pleomorphic presentation with certain clinical scenarios being “classic” fulminant often fatal acute mononucleosis due to EBV lymphoproliferation usually nonclonal recurrent infections with dysgammaglobulinemia or hypogammaglobulinemia typically have normal T and B cell numbers, normal proliferation, may have high IgA or IgM and low IgG, defective B cell memory generation

X-linked lymphoproliferative disease (XLP)
* 71 X-linked lymphoproliferative disease (XLP) diagnosis requires high index of suspicion, sometimes due to careful review of family history with X-linked pattern of illness detection of SAP protein by intracellular FACS or sequencing of SH2D1A gene can make the diagnosis fulminant EBV infection has an extremely poor outcome patients who develop hypogammaglobulinemia should be replaced HSCT may be considered in selected patients

Common variable immunodeficiency (CVID)
* 72 Common variable immunodeficiency (CVID) heterogeneous group of disorders with largely unknown molecular defects, typical onset in adults years clinical definition is “a genetic immune defect characterized by significantly decreased levels of IgG, IgA and/or IgM with poor or absent antibody production, with exclusion of genetic or other causes of hypogammaglobulinemia” unlike XLA, B cells detectable and patients often have defects in T cell number or function, predisposing to autoimmunity, granulomatous disease (lungs, intestine), and lymphoma

Common variable immunodeficiency (CVID)
* 73 Common variable immunodeficiency (CVID) Like other antibody deficiencies, sinopulmonary infections, chronic enteroviral meningoencephalitis are common Autoimmune disease especially ITP/AIHA is prominent* ITP 34% anti-IgA 5% Evans 12% SLE 4% AIHA 10% alopecia, DM, IBD, 3% each RA 7% pernicious anemia, myasthenia gravis, autoimmune neutropenia, primary biliary cirrhosis, immune urticaria treatment is IgG replacement and supportive treatment of infectious and autoimmune complications * Cunningham-Rundles. Autoimmunity in primary immune deficiency: taking lessons from our patients. Clin Exp Immunol (2011) vol. 164 Suppl 2 pp

Autoimmune lymphoproliferative syndrome (ALPS)
* 74 Autoimmune lymphoproliferative syndrome (ALPS) Lymphoproliferative disease caused by defects in pathways controlling apoptosis of lymphocytes Molecular defects increasingly understood, with majority due to germline heterozygous defects in FAS or somatic heterozygous defects in FAS (rarer: FASLG, CASP10, CASP8, NRAS) Chronic nonmalignant noninfectious lymphadenopathy and/or splenomegaly and elevated CD3+ CD4- CD8- TCRab cells (DN T cells) in blood (and also typically in LN biopsy) Autoimmune cytopenia very common and may be presenting symptom

Take home points about non-SCID immunodeficiencies
* 75 Take home points about non-SCID immunodeficiencies Boys with XLA lack B cells but have normal T cell function WAS is a triad of small low platelets, eczema, combined T and B cell dysfunction Boys with WAS are at risk for bleeding, infection, lymphoma, autoimmunity (i.e. these things can be elicited on family history) A boy that is super sick with EBV--think XLP Patients with antibody deficiencies (i.e. CVID) and ALPS frequently have autoimmune cytopenias

Explanation of the Tables that follow
76 Explanation of the Tables that follow These have been abstracted from the publication by International Union of Immunological Societies that is updated every several years Diseases in bold not already covered in the previous slides are in other sections’ content specifications (see arrow) were in previous content specifications (board questions still might occur, see arrow) are disorders I could see coming up Diseases not in bold are generally rarer and are not in content specifications, but you could potentially see in clinical practice or they are just too cool and interesting for me to skip Modified from Al-Herz W et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162.

Severe Combined Immunodeficiency
77 Severe Combined Immunodeficiency (B+ subtypes) Deficiency or Disease name Gene name XL/AR/AD T B Other features gc (common gamma chain) IL2RG X-linked - + NK - JAK3 AR IL7Ra IL7RA NK + CD45 PTPRC CD3d CD3D CD3e CD3z CD3Z Coronin-1-A CORO1A Migration defect, therefore thymus present

Severe Combined Immunodeficiency
78 Severe Combined Immunodeficiency (B- subtypes) Deficiency or Disease name Gene name XL/AR/AD T B Other features Recombinase activating gene 1 RAG1 AR - NK + Recombinase activating gene 2 RAG2 Artemis DCLRE1C NK +, radiation sensitivity Adenosine deaminase ADA NK -, rib flaring, hearing loss, neuro findings, pulmonary alveolar proteinosis DNA PKcs DNAPK Radiation sensitivity, microcephaly Reticular dysgenesis (adenylate kinase 2) AK2 Severe neutropenia, hearing loss

Combined Immunodeficiency (generally less severe than SCID)
79 Combined Immunodeficiency (generally less severe than SCID) Deficiency or Disease name Gene name XL/AR/AD Cell profile Ig profile Other features ZAP70 AR Nl CD4, CD8 T cell number, Nl B cell number Normal May have autoimmunity MHC class I TAP1, TAP2, TAPBP Nl CD4, CD8 T cell number Vasculitis, pyoderma gangrenosum MHC class II CIITA, RFX5, RFXAP, RFXANK  CD4, nl CD8 T cell number Nl or  Features like SCID, FTT, diarrhea, respiratory infections, liver/biliary disease Purine nucleoside phosphorylase PNP Progressive  Neurologic impairment CD3g CD3G Nl with  TCR expression Nl CD8 CD8A CD8 -, CD4 +

Combined Immunodeficiency (generally less severe than SCID)
80 Combined Immunodeficiency (generally less severe than SCID) Deficiency or Disease name Gene name XL/AR/AD Cell profile Ig profile Other features Wiskott-Aldrich syndrome WASP X-linked  T with age IgG  with age, poor specific Ab, low isohem Thrombocytopenia, small platelets, eczema, autoimmunity, lymphoma SLAM-associated protein (SAP, XLP type 1) SH2D1A Normal T and B #, reduced memory B May have hypogamm, poor specific Ab EBV related lymphoproliferation, fatal mono, HLH, absent NK-T cells X-linked inhibitor of apoptosis (XLP type 2) BIRC4 Normal T and B # EBV related lymphoproliferation, HLH, colitis, IBD Ataxia-telangiectasia mutated ATM  T with age, Nl B # May have  Ataxia, radiosensitivity, telangiectasia, lymphoproliferation

Combined Immunodeficiency (with other major anomalies)
81 Combined Immunodeficiency (with other major anomalies) Deficiency or Disease name Gene name XL/AR/AD Cell profile Ig profile Other features Digeorge (lack of thymus organ development) Deletion of 22q11.2 incl TBX1 AD or sporadic  T cell #, in complete can be like SCID, nl B cell # Variably  Cardiac, jaw, hypocalcemia; autoimmunity CHARGE (coloboma, heart, atresia choanae, retarded growth, genital, ear) CHD7, some unknown Hearing loss, hypocalcemia, swallowing defect CID with multiple intestinal atresia TTC7A AR  T cell #, in complete can be like SCID  Multiple intestinal atresias, polyhydramnios Cartilage-hair hypoplasia (RNA component of mitochondrial RNA processing endoribonuclease) RMRP Short-limbed dwarfish, sparse hair, anemia, BM failure, lymphoma

Hyper-IgM syndromes 82 Deficiency or Disease name Gene name XL/AR/AD
Cell profile Ig profile Other features CD40 ligand (X-linked hyper-IgM) CD40LG X-linked Nl T and B #, lack of isotype switching IgM nl or , other isotypes  Neutropenia, opportunistic infections (T cell functional defect), liver and biliary tract disease CD40 AR Ectodermal dysplasia with immunodeficiency IKGKB (NEMO) Nl T and B #, lack of isotype switching, susceptible to mycobacteria Conical teeth, lack of sweat glands and skin appendages, frontal bossing Activation-induced cytidine deaminase (AID) AICDA Nl T and B #, lack of isotype switching; normal T cell function Lymphadenopathy due to hyperplastic germinal centers Uracil-N-glycosylase UNG Like AID

Predominantly antibody deficiency
83 Predominantly antibody deficiency Deficiency or Disease name Gene name XL/AR/AD B cells Ig profile Bruton’s tyrosine kinase BTK X-linked - All isotypes  Components of pre-BCR and BCR (m heavy chain, l5, Iga, Igb) AR Other components of pre-BCR and BCR signaling (BLNK, PI3 kinase, E47 transcription factor) BLNK, PIK3R1, TCF3 MDS with hypogammaglobinemia May be associated with monosomy 7, trisomy 8 DC variable One or more isotypes  Thymoma associated Unknown

Predominantly antibody deficiency (CVID and other syndromes)
84 Predominantly antibody deficiency (CVID and other syndromes) Deficiency or Disease name Gene name XL/AR/AD Features Common variable immunodeficiency Unknown Low IgG and either low IgA and/or low IgM Cell surface molecules involved in BCR signaling CD19, CD81, CD20, CD21 AR Presents as CVID Growth factor receptors for B cells TACI, BAFF receptor Selective IgA deficiency Variable Usually asymptomatic, may have infections, poor Ab response to carbohydrate, may have allergies or autoimmune disease Transient hypogammaglobulinemia of infancy Low IgG and IgA, may be an exaggerated “nadir,” typically make responses to vaccines, usually not associated with significant infections Isolated IgG subclass deficiency Usually asymptomatic, a minority may have poor Ab response and infections

Complement deficiencies
85 Complement deficiencies I truly know next to nothing about these but people keep asking me to include them Deficiency Gene XL/AR/AD Pathway Infections? Auto-immunity? Other C1q, C1r, C1s C1QA, C1QB, C1QC, C1R, C1S AR Classical Encapsulated SLE C4 C4A. C4B C2 atherosclerosis C3 AR or AD Central Yes glomerulonephritis C5, C6, C7, C8a-g, C8b, C9 C5, C6, C7, C8A, C8G, C8B, C9 Terminal Neisseria -

Complement pathway defects
86 Complement pathway defects I truly know next to nothing about these but people keep asking me to include them Protein Gene XL/AR/AD Effect Infections? Auto-immunity? Other C1 inhibitor SERPING1 AD Activation, consumption of C4/C2, bradykinin - Hereditary angioedema Factor B CFB Gain of function AD alternative pathway Atypical HUS Factor D CFD AR Defect in alternative Neisseria Properdin CFP X-linked Factor I CFI alternative, consumption of C3 Neisseria, other Membrano-proliferative glomerulonephritis Atypical HUS, pre-eclampsia Factor H CFH

Finally--2 slides on AIDS
* 87 Finally--2 slides on AIDS 90% of infants/children acquire perinatally, typically no symptoms virus preferentially infects CD4 T lymphocytes, progressively depleted by direct toxicity, thymic atrophy, destruction of infected CD4 T cells by the immune system viral entry is mediated by the CD4 protein itself along with the chemokine receptor CXCR4 can also infect monocytes, which may act as a reservoir screening of infants of mothers with HIV is problematic because Maternal antibody is placentally transferred (may circulate up to 18 months) CD4 T cell depletion is not always apparent in the face of normally increased CD4 counts in infants Diagnosis much be made on the basis of antigen testing (p24), HIV NAT (DNA PCR) and/or viral load (RNA levels)

Finally--2 slides on AIDS
* 88 Finally--2 slides on AIDS Hematologic/immunologic manifestations: anemia (multifactorial including viral suppression, drugs, drugs, drugs, anemia of chronic disease, autoimmune, nutritional) thrombocytopenia (less multifactorial including ITP, drugs, TTP, bone marrow infections such as MAI) immune Depletion of CD4 T cells B cell dysregulation including excess numbers of B cells and extreme hypergammaglobulinemia Malignancies in children with HIV: NHL systemic or primary CNS large cell, small noncleaved, MALT, plasmacytoid leiomyosarcoma/leiomyoma (children > adults) ALL Kaposi’s sarcoma (children < adults)

Selected References Koh AY, Pizzo PA. Fever and Granulocytopenia, and Infections in Children with Cancer. In: Long SS, Pickering LK, Prober CG, editors. Principles and Practice of Pediatric Infectious Diseases Koh AY, Pizzo PA. Infectious Disease in Pediatric Cancer Survivors. In: Nathan and Oski 7th edition Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. CLIN INFECT DIS Feb 15;52(4):e56–e93. Dvorak CC and Steinbach WJ. Opportunistic infections in hematopoietic stem cell transplantation. In: Feigin, Cherry, Demmler-Harrison, Kaplan, editors. Textbook of Pediatric Infectious Diseases, 8th edition. Prepublication. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontonyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, Van Burik JV, Wingard JR, Patterson TF. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis (3): Bonilla FA, Geha RS. Primary Immunodeficiency Diseases. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, editors. Hematology of Infancy and Childhood. Philadelphia: WB Saunders; p (also new edition 2009) Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WCJ, Groeneveld K, Hooijkaas H, van Dongen JJM. Immunophenotyping of blood lymphocytes in childhood Journal of Pediatrics 130 (3): Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem. 1982;28(1):126–8. Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162. Cunningham-Rundles. How I treat common variable immune deficiency. Blood (2010) vol. 116 (1) pp. 7-15 Cunningham-Rundles. Autoimmunity in primary immune deficiency: taking lessons from our patients. Clin Exp Immunol (2011) vol. 164 Suppl 2 pp. 6-11 Oliveira et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood (2010) vol. 116 (14) pp. e35-40 91

Key to slides and content specifications
II. Leukocytes C. Lymphocytes 1. Normal morphology and age related values 3,22,25-29,36 2. Surface membrane antigens and gene rearrangements 3,21,25-28 3. Kinetics 25-26 4. Biochemistry 46-54 5a.1. B cells Immunoglobulins 3,11,23,25-26,30-36 5b.1. T cells and T cell receptor 3,22,23,25-26,30 5b.2. NK cells 3,21,28 5b.3. Major Histocompatibility/Antigen presentation 3,11,23,79 6. Lymphocytosis 28-29 7. Lymphopenia 28-29,41-57 8. Mononucleosis Did not include

Key to slides and content specifications
VI: Immunologic Abnormalities A. Infections in Immunocompromised patients 1. Prophylaxis (Bacterial, Fungal, Viral, Pneumocystis 7, 9-20 2. Treatment of infection in immunocompromised patients (Bacterial, Fungal, Viral, Pneumocystis) B. Immunodeficiency states 1. Congenital immunodeficiencies a. Clinical features and inheritance See each disorder and tables b. Relationship with cancer 23,24,64,70-73 ,78-80 c.1. Wiskott-Aldrich syndrome 64-67, 75,80 c.2. Disorders of immunoglobulin production 59-62, 68-69, 72-73,82-84 c.3. Severe Combined Immunodeficiency 41-57, 77-78,81 c.4. X-linked lymphoproliferative disease 70-71, 75,80 2. Acquired immunodeficiency syndrome (AIDS) 87-88 C. Autoimmune lymphoproliferative syndrome 74, other lectures

Questions? E-mail: Sung-Yun.Pai@childrens.harvard.edu
Immunology and Immunodeficiency for the Pediatric Hematologist-Oncologist Questions? 94

Immunology and Immunodeficiency for the Hematologist-Oncologist

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