For seven decades, the pathophysiology of Good's syndrome (GS) has remained a mystery, with few attempts to solve it. Initially described as an association between hypogammaglobulinemia and thymoma, ...controversy exists whether this is a unique disease, or a subgroup of Common Variable Immune Deficiency (CVID). Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history. In this mini review, we discuss current state of the art data and identify research gaps. In order to resolve controversies and fill in knowledge gaps, we propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease. We hope this novel approach sets a clear direction to solve the current controversies.
Abstract
Background
Evaluating age as a risk factor for susceptibility to infectious diseases, particularly coronavirus disease 2019 (COVID-19), is critical. Cytomegalovirus (CMV) serologic ...prevalence increases with age and associates with inflammatory-mediated diseases in the elderly. However, little is known regarding the subclinical impact of CMV and risk it poses to healthy older adults. Prior to the COVID-19 pandemic we conducted a study to determine the association of CMV to biologic age and immune dysregulation.
Methods
Community-dwelling, healthy adults older than 60 years were evaluated using DNA methylation assays to define epigenetic age (EpiAge) and T-cell immunophenotyping to assess immune dysregulation.
Results
All subjects were healthy and asymptomatic. Those CMV seropositive had more lymphocytes, CD8 T cells, CD28− T cells, decreased CD4:CD8 cell ratios, and had higher average EpiAge (65.34 years) than those CMV seronegative (59.53 years). Decreased percent CD4 (P = .003) and numbers of CD4 T cells (P = .0199) correlated with increased EpiAge.
Conclusions
Our novel findings distinguish altered immunity in the elderly based on CMV status. Chronic CMV infection in healthy, older adults is associated with indicators of immune dysregulation, both of which correlate to differences in EpiAge.
Age is a risk factor for infectious disease susceptibility and poor vaccine responses. Our novel findings in CMV seropositive healthy older adults better define age as a biologic variable and distinguish compromised immunity in the elderly based on CMV status.
Despite successful treatment and CD4+ T-cell recovery, HIV-infected individuals often experience a profound immune dysregulation characterized by a persistently low CD4:CD8 T-cell ratio. This ...residual immune dysregulation is reminiscent of the Immune Risk Phenotype (IRP) previously associated with morbidity and mortality in the uninfected elderly (>85 years). The IRP consists of laboratory markers that include: a low CD4:CD8 T-cell ratio, an expansion of CD8+CD28- T-cells and cytomegalovirus (CMV) seropositivity. Despite the significant overlap in immunological phenotypes between normal aging and HIV infection, the IRP has never been evaluated in HIV-infected individuals. In this pilot study we characterized immune changes associated with the IRP in a sample of successfully treated HIV-infected subjects.
18 virologically suppressed HIV-infected subjects were categorized into 2 groups based on their IRP status; HIV+IRP+, (n = 8) and HIV+IRP-, (n = 10) and compared to 15 age-matched HIV uninfected IRP negative controls. All individuals were assessed for functional and phenotypic immune characteristics including: pro-inflammatory cytokine production, antigen-specific proliferation capacity, replicative senescence, T-cell differentiation and lymphocyte telomere length.
Compared to HIV-infected subjects without an IRP, HIV+IRP+ subjects exhibited a higher frequency of TNF-α-producing CD8+ T-cells (p = 0.05) and a reduced proportion of CD8+ naïve T-cells (p = 0.007). The IRP status was also associated with a marked up-regulation of the replicative senescence markers CD57 and KLGR1, on the surface of CD8+T-cells (p = 0.004). Finally, HIV+IRP+ individuals had a significantly shorter mean lymphocyte telomere length than their non-IRP counterparts (p = 0.03).
Our findings suggest that, despite similar levels of treatment-mediated viral suppression, the phenotypic and functional immune characteristics of HIV+IRP+ individuals are distinct from those observed in non-IRP individuals. The IRP appears to identify a subset of treated HIV-infected individuals with a higher degree of immune senescence.
Good's syndrome (GS) is a rare immune deficiency described almost 6 decades ago. Despite numerous published individual case reports and data collected in cross-sectional studies of small cohorts, the ...natural history and long-term outcomes of this disease remain unknown.
We aimed to determine the clinical and laboratory evolution of 8 adults diagnosed with GS and consecutively evaluated between 1983 and 2023.
In this prospective, longitudinal cohort study, newly diagnosed patients with GS were followed through repeated measures of clinical, immune, and hematologic changes, as well as targeted genetic screening.
All patients reported a healthy childhood and adolescence with symptom onset during the third or fourth decade of life. All presented to our center with recurrent bacterial sinopulmonary infections, thymoma, hypogammaglobulinemia, and absence of B cells. The median age of GS diagnosis was 57 years. During follow-up, immunoglobin replacement therapy effectively minimized sinopulmonary infections. However, the majority experienced severe and systemic viral or fungal infections, 3 developed basal cell carcinomas, and 5 had progressive bronchiectasis and persistent splenomegaly. The most notable clinical feature was opportunistic infections and in vitro evidence of cellular immune deficiency, which resulted in the death of 2 individuals. We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure.
Knowledge of the unique phenotype and temporal evolution of GS has allowed us to develop a more comprehensive diagnostic framework. It can be investigated as part of broader research into disease pathophysiology.
Natural killer (NK) cell activity is increased in individuals who remain uninfected despite repeated exposures to HIV. Given that a combined major histocompatibility complex (MHC) class I and killer ...immunoglobulin-like receptor (KIR) KIR3D genotype has been linked to rate of HIV disease progression, we assessed whether these genotypes played a role in protection from infection.
The study genotyped 80 HIV-exposed uninfected (EU) and 304 subjects in HIV primary infection (PI) at the MHC class IB and KIR3DS/L1 loci.
KIR3D genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed by sequence-specific oligonucleotide polymerase chain reaction and sequencing to resolve Bw4 and Bw6 alleles and the amino acid present at position 80.
Comparison of the genetic distribution of KIR3D, HLA Bw4 and HLA Bw4-I80 genotypes in EU versus PI subjects reveal an increased proportion of KIR3DS1 homozygotes in EU (11/80, 13.8%) compared to subjects in PI (16/304, 5.3%). Analyses of combined MHC class I and KIR3D expression show no differences between the two populations.
Homozygosity for the activating NK receptor KIR3DS1, may contribute to the more active NK cell function observed in EU and their relative resistance to HIV infection.
Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss ...of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype.
We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP).
Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio.
Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.
Natural killer (NK) cells play a role in the clearance of viral infections. Combinations of alleles at the polymorphic HLA-B locus and the NK cell surface killer immunoglobulin-like receptor locus ...KIR3DL1/S1 have been shown to influence time to AIDS in HIV-infected individuals and risk of seroconversion in HIV exposed seronegative (HESN) subjects. Here, we assessed time to seroconversion or duration of seronegative status in a group of 168 HIV exposed individuals, including 74 seroconverters and 94 HESN based on carriage or not of KIR3DL1/S1/HLA-B genotypes previously shown to be associated with protection from infection and/or slow time to AIDS. KIR3DL1/S1 genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed to four-position resolution to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. KIR3DL1/S1 heterozygotes became HIV infected significantly faster than KIR3DS1 homozygotes. Individuals who carried both KIR3DS1 and Bw4*80I did not remain HIV seronegative longer than those from a control group who were homozygous for HLA-Bw6 and carried no HLA-A locus Bw4 alleles Subjects who were *h/*y+B*57 showed a trend towards slower time to serconversion than those with other KIR3DL1 homozygous and KIR3DL1/S1 heterozygous genotypes. Thus, KIR3DS1 homozygosity is associated with protection from HIV infection while co-carriage of KIR3DS1 and Bw4*80I is not. The requirements for protection from HIV infection can differ from those that influence time to AIDS in HIV infected individuals.
Previously, we showed that Killer Immunoglobulin-like Receptor (KIR)3DS1 homozygotes (hmz) are more frequent in HIV exposed seronegative (HESN) than in recently HIV infected (HIV+) individuals. ...KIR3DS1 encodes an activating Natural Killer (NK) cell receptor (NKR). The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.
Coexpression of certain combinations of natural killer cell receptor KIR3DL1 and HLA-B alleles is associated with slower time to AIDS. The strongest protection in terms of disease outcome in KIR3DL1 ...homozygotes (3DL1 hmz) is coexpression of HLA-B*57 and a set of KIR3DL1 genotypes (3DL1*h/*y) lacking alleles expressed at low levels on natural killer cells. We questioned whether this allele combination could also influence resistance to infection.
The genetic distribution of 3DL1*h/*y and HLA-B*57 was compared in 41 HIV-exposed uninfected and 186 recently HIV-infected 3DL1 hmz.
KIR3DL1 subtyping was performed by sequencing the exons 3, 4, 5, 7-9. The major histocompatibility complex class IB locus was typed by sequence specific oligonucleotide PCR and sequencing to resolve Bw4 and Bw6 alleles and the amino acid present at position 80.
Percentage carriers of HLA-B*57 in HIV-exposed uninfected and individuals in a primary infection cohort was 12.2 and 4.3%, respectively (P = 0.0631), whereas that of 3DL1*h/*y was similar in both populations (P = 0.221). The 3DL1*h/*y-HLA-B*57 combined genotype was more frequent in exposed uninfected individuals (12.2%) than individuals in primary infection (2.7%) (P = 0.019; odds ratio, 5.03; 95% confidence intervals, 1.38-18.3).
Coexpression of 3DL1*h/*y and B*57, which has been associated with a reduced risk of progressing to AIDS in HIV-infected individuals also lowers the risk of HIV infection in exposed uninfected individuals.
NKG2C is an activating NK cell receptor encoded by a gene having an unexpressed deletion variant. Cytomegalovirus (CMV) infection expands a population of NKG2C
NK cells with adaptive-like properties. ...Previous reports found that carriage of the deleted
variant was more frequent in people living with HIV (PLWH) than in HIV
controls unexposed to HIV. The frequency of NKG2C
NK cells positively correlated with HIV viral load (VL) in some studies and negatively correlated with VL in others. Here, we investigated the link between
genotype and HIV susceptibility and VL set point in PLWH. NKG2C genotyping was performed on 434 PLWH and 157 HIV-exposed seronegative (HESN) subjects. Comparison of the distributions of the three possible
genotypes in these populations revealed that the frequencies of
and
carriers did not differ significantly between PLWH and HESN subjects, while that of
carriers was higher in PLWH than in HESN subjects, in which none were found (
= 0.03, χ
test). We were unable to replicate that carriage of at least 1
allele was more frequent in PLWH. Information on the pretreatment VL set point was available for 160
, 83
, and 6
PLWH. HIV VL set points were similar between
genotypes. The frequency of NKG2C
CD3
CD14
CD19
CD56
NK cells and the mean fluorescence intensity (MFI) of NKG2C expression on NK cells were higher on cells from CMV
PLWH who carried 2, versus 1,
alleles. We observed no correlations between VL set point and either the frequency or the MFI of NKG2C expression.
We compared
allele and genotype distributions in subjects who remained HIV uninfected despite multiple HIV exposures (HESN subjects) with those in the group PLWH. This allowed us to determine whether
genotype influenced susceptibility to HIV infection. The absence of the
genotype among HESN subjects but not PLWH suggested that carriage of this genotype was associated with HIV susceptibility. We calculated the VL set point in a subset of 252
-genotyped PLWH. We observed no between-group differences in the VL set point in carriers of the three possible
genotypes. No significant correlations were seen between the frequency or MFI of NKG2C expression on NK cells and VL set point in cytomegalovirus-coinfected PLWH. These findings suggested that adaptive NK cells played no role in establishing the in VL set point, a parameter that is a predictor of the rate of treatment-naive HIV disease progression.
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