Immunodeficiency and Autoimmunity€¦ · Case 2 Presented initially aged 19 in 2007 with severe autoimmune haemolytic anaemia Also found to be hypogammaglobulinaemic: IgG of 2.81,

Immunodeficiency

and AutoimmunityJOCELYN JIANG

WESTMEAD HOSPITAL ICPMR

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

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 Plaquenildaily with T cell count increasing to 0.82 x 10^9/L

Currently being monitored for recurrence, has remained well over 2 years

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 westmeadchildren’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

Case 2

Examination findings:

Prominent facial acne – likely

secondary to steroids

Normal

cardio/respiratory/abdominal

examination

No lymphadenopathy

Imaging:

HRCT chest: minor presumed reactive lymphadenopathy, stable on CT from 2007-2010

Lung function testing –mod obstructive deficit no bronchodilator associated response DLCO 92% and alveolar volume 88% predicted

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%

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 4th 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

Monogenic affects on

autoimmunity

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?)

• 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

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

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

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

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?

Summary

Overlap between autoimmunity and immunodeficiency

Immune dysregulation

Break down of mechanisms of central and peripheral tolerance

Autoimmunity itself can cause cytopenias including lymphopenia

Acknowledgments

Prof Matthew Cook

Dr Ming-Wei LIn

Questions?