Immunodeficiency and Autoimmunity

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1 Immunodeficiency and Autoimmunity JOCELYN JIANG WESTMEAD HOSPITAL ICPMR

2 Case 1 42 year old woman referred for investigation for lymphopenia Incidental finding on routine bloods Lymphocyte count 0.5 x 10^9/L repeated on several occasions and low Well no recurrent or opportunistic infections No recent vaccinations; no history of blood transfusions Never had any immunosuppressant (includintg oral steroids) Serum immunoglobulins within normal limits PHx: psoriasis PRN topical therament, well controlled, lactase deficiency, seasonal rhinitis Examination: No significant findings; no palpable peripheral lymphadenopathy Investigations: CD4 and CD8 lymphopenia CD19 B cells in normal limits but lacking memory B cells Normal serum electrophoresis and serum light chains Complement in normal limits Normal thyroid function and EUC Intact specific IgG responses

3 Further investigations CT chest to check for lymphadenopathy: bilateral hilar and mediastinal lymphadenopathy Biopsy confirmed sarcoidosis, ACE 45 U/L. Dry cough started soon after biopsy Trial of corticosteroids (prednisolone 25mg daily for 2 weeks) cough resolve and wheeze Subtle increase in lymphocyte count after commencement of steroids and this continued to improve on 400mg Plaquenil daily with T cell count increasing to 0.82 x 10^9/L Currently being monitored for recurrence, has remained well over 2 years

4 Case 2 Presented initially aged 19 in 2007 with severe autoimmune haemolytic anaemia Also found to be hypogammaglobulinaemic: IgG of 2.81, IgA and IgM also reduced Low level of anti tetanus of 0.12 Lymphocyte count 0.4 with immunosuppression for haemolytic anaemia (now within normal ranges) No history of severe infection but has had monthly upper respiratory tract infection and occasional sinus infection. Constant sore throat/cough No history of pneumonia, gut infection, nail infection, single wart on right index finger PHx: Global intellectual disability managed by the child development unit at westmead children s hospital ADHD Childhood seizures VSD repaired Mild asthma No thymus noted as a child Checked for DiGeorge Syndrome exclude by FISH FHx: no significant medical conditions

5 Case 2 Examination findings: Prominent facial acne likely secondary to steroids Normal cardio/respiratory/abdominal examination No lymphadenopathy CVID panel: Frieburg Ia; MB0, Euroclas: B=/smB-CD210lo/Tr-lo: Total B cells 3.46% (L) Memory B cells 6.65% (L) Switched Memory B Cells (0.04% of PBLS 1.18% of B cells) CD21-lo cells: 22.91% Imaging: HRCT chest: minor presumed reactive lymphadenopathy, stable on CT from Lung function testing mod obstructive deficit no bronchodilator associated response DLCO 92% and alveolar volume 88% predicted

6 Case 2: Progress Commenced on IVIg for CVID Symptoms of constant URTI completely resolved Only 2 courses of antibiotics since that time Bactrim and penicillin V prophylaxis for low CD4 count and post splenectomy. Bactrim eventually ceased Continued to have a stormy course with recurrent thrombocytopenia failed steroids, cyclophosphamide, rituximab, splenectomy After fourth relapse of ITP with platelets as low as 2, was started on romiplostim Good response initially, then relapsed in 2012 and became refractory Change to oral eltromopag 25mg 4 th episode of thrombocytopenia in 2012 Good response to eltrombopag but recent relapse (platelets 2, no response to IVIg) and now back on 100mg prednisolone; eltromboplag dose increased to 50mg

7 Monogenic affects on autoimmunity The association between immunodeficiency and autoimmunity is well described n the literature Often in PID: failure to respond to non self pathogens while reacting to self pathogens Central tolerance: deletion of self reactive T-cells in the thymus AIRE mutation: autoimmunity and antibodies to Th-17 related cytokines DiGeorge Syndrome: can have SCID, BUT 30% have mild-mod lymphopenia, lack of thymic regulation, decreased T regs Peripheral tolerance: self reactive T cells that escape central tolerance check points remain unresponsive in peripheral organs IPEX mutation in FOXP3 that is lineage defining for Tregs: immunodysregulation, polyendocrinopathy and enteropathy CD25 deficiency clinical phenotype similar to IPEX. CD25 mops up IL-2 and/or generation of inducible T-regs CTLA4 deficiency CTLA4 removes immune activating B7 molecules from APCs Increased activated effector T cells increased T cell counts decreased B cell counts and hypogammglobulinaemia (via T cell invasion or B cell overstimulation?)

8 However, other areas of immune tolerance breakdown are described for different PIDs Lymphopenia and impaired natural selection process for lymphocytes RAG deficiency with low frequency B and T cells impaired natural selection process? Omen syndrome: autoreactive T cells causing a graft v host disease Decreased levels of AIRE and increased BAFF; lack of B cell competition for autoreactive cells Failure of apoptosis ALPS: FAS-deficiency Importance of apoptosis in controlled reaction of proliferating cells after antigen recognition various autoimmune features including ANA and RhF positivity Polymorphisims in FAS/FASL genes associated with SLE STAT1 GOF (with increased interferon alpha) STAT3 GOF mutations (observed decreased T regs, possibly through signalling via SOCS3?) Hyper activation of lymphocytes: PI3K, PLC gamma, PKC gamma deficiency Breakdown of B cell tolerance AID deficiency and deficiencies in central and peripheral B cell check point tolerance DOCK8 deficiency decreased T reg cells and T reg activity

9 CVID Heterogenous condition: marked decrease in IgG after the age of 2 years, absent isohaemagglutinins and/or poor response to vaccines, recurrent sinopulmonary infections >25% of patients also have autoimmune or autoinflammatory features: ITP, haemolytic anaemia Cytopenia associated with splenomegally Vitiligo, APLs, RA, SLE, vasculitis also reported Granulomatous disease that can mimic sarcoidosis

10 CVID: autoimmunity mechanisms? Multiple mechanisms???? mixed bag Patients with reduced numbers of switched memory B cells and an increased proportion of CD21lo cells have increased proportion of splenomegaly and autoimmunity Immune dysregulation? The role of T cells? Increased naïve T cells Decreased Tregs Impaired differentiation, maturation and function of dendritic cells were reported to be involved Abnormalities of cytokines

11 Lessons from systemic autoimmunity Considerable overlap between genes associated with increased rheumatoid arthritis risk and PID E.g. Caspase 8, Caspase 10, AIRE, IL-2RA, PTPR, RAG1, RAG2 SLE strong genetic and environmental contribution Failure to clear apoptotic debris e.g. complement deficiencies (C1q, C2, C4; polymorphic variants of FcyIIB and FcyIIB and the rs1205 variant of CRP, the R77H variant of integrin alpha M) Interferon-alpha pathways GOF mutations that increase IFN-alpha pathways are associated with SLE (TREX1) Increased IFN-alpha also described in patients with CVID with inflammatory complications Issues with immune system transduction pathways Lymphopenia is a frequent observation in sarcoidosis Unclear if associated with increased infections Sequestration in tissue granulomas?

12 Summary Overlap between autoimmunity and immunodeficiency Immune dysregulation Break down of mechanisms of central and peripheral tolerance Autoimmunity itself can cause cytopenias including lymphopenia

13 Acknowledgments Prof Matthew Cook Dr Ming-Wei LIn

14 Questions?